U.S. patent application number 15/711902 was filed with the patent office on 2018-03-29 for phosphatidylinositol 3-kinase inhibitors.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Jayaraman Chandrasekhar, Leena Patel, Stephane Perreault, Gary Phillips, Nicholas Alexander Till, Jennifer Anne Treiberg.
Application Number | 20180086768 15/711902 |
Document ID | / |
Family ID | 60002112 |
Filed Date | 2018-03-29 |
United States Patent
Application |
20180086768 |
Kind Code |
A1 |
Chandrasekhar; Jayaraman ;
et al. |
March 29, 2018 |
PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS
Abstract
The present application provides the compounds of formula I
##STR00001## or pharmaceutically acceptable salts, isomers,
tautomer, or a mixture thereof, wherein s, t, n, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as described herein.
Inventors: |
Chandrasekhar; Jayaraman;
(Redmond, WA) ; Patel; Leena; (Seattle, WA)
; Perreault; Stephane; (Brier, WA) ; Phillips;
Gary; (Issaquah, WA) ; Till; Nicholas Alexander;
(Bainbridge Island, WA) ; Treiberg; Jennifer Anne;
(Redmond, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
60002112 |
Appl. No.: |
15/711902 |
Filed: |
September 21, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62398789 |
Sep 23, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 487/02 20130101;
A61P 29/00 20180101; A61P 35/02 20180101; C07D 417/14 20130101;
A61K 31/4196 20130101; C07D 487/04 20130101; A61K 31/519 20130101;
A61P 13/12 20180101; C07D 413/14 20130101; A61P 35/00 20180101;
A61K 31/4409 20130101; A61K 31/4184 20130101; A61P 9/00 20180101;
A61K 31/4709 20130101; A61P 37/00 20180101; C07D 401/14 20130101;
A61K 31/506 20130101; C07D 403/14 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 417/14 20060101 C07D417/14; C07D 413/14 20060101
C07D413/14; C07D 403/14 20060101 C07D403/14 |
Claims
1. A compound having the structure of formula (I): ##STR00227##
wherein n is 1, 2, 3 or 4; s is 1 or 2; t is 1 or 2; each R.sup.1
is independently selected from hydrogen, halo, cyano, hydroxy,
amino, --C(O)R.sup.a, --C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b,
--N(R.sup.a)C(O)R.sup.b, --S(O)NR.sup.aR.sup.b,
--S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g, --S(O).sub.2R.sup.g,
--NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S, and
4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S; wherein each C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10 membered
heterocyclyl is optionally substituted with one to four R.sup.100;
R.sup.2 is selected from hydrogen, halo, cyano, hydroxy, amino,
--C(O)R.sup.a, --C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b,
--N(R.sup.a)C(O)R.sup.b, --S(O)NR.sup.aR.sup.b,
--S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g, --S(O).sub.2R.sup.g,
--NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S, and
4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S; wherein each C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10 membered
heterocyclyl is optionally substituted with one to four R.sup.101;
R.sup.3 is selected from hydrogen, halo, cyano, hydroxy, amino,
--C(O)R.sup.a, --C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b,
--N(R.sup.a)C(O)R.sup.b, --N(R.sup.a)C(O)NR.sup.aR.sup.b,
--OC(O)NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2R.sup.a, --S(O)NR.sup.aR.sup.b,
--S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g, --S(O).sub.2R.sup.g
--NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S, and
4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S; wherein each C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10 membered
heterocyclyl is optionally substituted with one to four R.sup.102;
R.sup.4 is a 5-10 membered heteroaryl; wherein said 5-10 membered
heteroaryl is optionally substituted with one to four R.sup.103;
each R.sup.5 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--N(R.sup.a)C(O)NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; wherein each
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10
membered heterocyclyl is optionally substituted with one to four
R.sup.104; each R.sup.6 is independently selected from hydrogen,
halo, cyano, hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; each
R.sup.a and R.sup.b is independently selected from hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; wherein
each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, is
optionally substituted with one to four R.sup.200; each R.sup.100,
R.sup.101, R.sup.102, R.sup.103 and R.sup.104 is independently
selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo,
vinyl, --C(O)R.sup.c, --C(O)OR.sup.c, --C(O)NR.sup.cR.sup.d,
--N(R.sup.c)C(O)R.sup.d, --N(R.sup.a)C(O)NR.sup.aR.sup.b,
--OC(O)NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2R.sup.a, --S(O)NR.sup.cR.sup.d,
--S(O).sub.2NR.sup.cR.sup.d, --S(O)R.sup.g, --S(O).sub.2R.sup.g,
--NR.sup.cR.sup.d, --OR.sup.c, --SR.sup.d, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10 membered
heterocyclyl; wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl and 4-10 membered heterocyclyl is optionally
substituted with one to four R.sup.201; each R.sup.c and R.sup.d is
independently selected from hydrogen, C.sub.6-10 aryl, C.sub.1-6
alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; each R.sup.200 and
R.sup.201 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, oxo, thioxo, vinyl, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --N(R.sup.e)C(O)R.sup.f,
--S(O)NR.sup.eR.sup.f, --S(O).sub.2NR.sup.eR.sup.f, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.eR.sup.f, --OR.sup.e, --SR.sup.e,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; each
R.sup.e and R.sup.f is independently selected from hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; each
R.sup.g is independently selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S, and 4-10 membered
heterocyclyl containing 1 to 4 heteroatoms selected from the group
consisting of N, O, and S; wherein each C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl and 4-10 membered heterocyclyl is
optionally substituted with one to four R.sup.200; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
2. The compound of claim 1 having the structure of formula IA:
##STR00228## wherein n, s, t, R.sup.1, R.sup.2, R.sup.4, R.sup.5
and R.sup.6 are as defined above; X.sup.1 is N or C; each X.sup.2,
X.sup.3, X.sup.4 and X.sup.5 is independently selected from S, O,
CR.sup.10 and NR.sup.11; wherein each R.sup.10 is independently
selected from hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; wherein each
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10
membered heterocyclyl is optionally substituted with one to four
R.sup.104; wherein each R.sup.11 is independently selected from
absent, hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; alternatively,
one R.sup.10 and one R.sup.11 group, together with the atoms to
which they are attached form a five, six or seven membered fused,
or bridged ring; or a pharmaceutically acceptable salt, isomer, or
a mixture thereof.
3. The compound of claim 1, wherein R.sup.3 is selected from:
##STR00229## wherein t is 1 or 2; wherein each R.sup.13 is
independently selected from hydrogen, halo, cyano, hydroxy, amino,
--C(O)R.sup.a, --C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b,
--N(R.sup.a)C(O)R.sup.b, --S(O)NR.sup.aR.sup.b,
--S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g, --S(O).sub.2R.sup.g,
--NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S, and
4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S; or a pharmaceutically
acceptable salt, isomer, or a mixture thereof.
4. The compound of claim 1 having the structure of formula IB:
##STR00230## wherein each R.sup.13 is independently selected from
hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
5. The compound of claim 1 having the structure of formula IC:
##STR00231## wherein each R.sup.13 is independently selected from
hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
6. The compound of claim 1 having the structure of formula ID:
##STR00232## or a pharmaceutically acceptable salt, isomer, or a
mixture thereof.
7. The compound of claim 1 having the structure of formula IE:
##STR00233## wherein each R.sup.13 is independently selected from
hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
8. The compound of claim 1 having the structure of formula IF:
##STR00234## or a pharmaceutically acceptable salt, isomer, or a
mixture thereof.
9. The compound of claim 1 having the structure of formula IG:
##STR00235## or a pharmaceutically acceptable salt thereof; wherein
the atropisomer of formula IE or a pharmaceutically acceptable salt
thereof, is present in excess of its corresponding enantiomer or a
pharmaceutically acceptable salt thereof.
10. The compound of claim 1 having the structure of formula IH:
##STR00236## wherein each R.sup.13 is independently selected from
hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
11. The compound of claim 1 having the structure of formula IJ:
##STR00237## or a pharmaceutically acceptable salt, isomer, or a
mixture thereof.
12. The compound of claim 1, wherein R.sup.4 is selected from the
table below: ##STR00238## or a pharmaceutically acceptable salt,
isomer, or a mixture thereof.
13. The compound of claim 1, wherein R.sup.1 is selected from
hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl,
butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,
difluoroethyl and trifluoroethyl; or a pharmaceutically acceptable
salt, isomer, or a mixture thereof.
14. The compound of claim 1, wherein R.sup.2 is C.sub.1-6 alkyl,
C.sub.3-8 cycloalkyl, 5-6 membered heteroaryl containing 1 to 3
heteroatoms selected from the group consisting of N, O, and S, and
4-6 membered heterocyclyl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S; wherein each C.sub.1-6
alkyl, C.sub.3-8 cycloalkyl, 5-6 membered heteroaryl and 4-6
membered heterocyclyl is optionally substituted with one to four
R.sup.101; or a pharmaceutically acceptable salt, isomer, or a
mixture thereof.
15. The compound of claim 1, wherein R.sup.3 is selected from 5-10
membered heteroaryl containing 1 to 4 heteroatoms selected from the
group consisting of N, O, and S, --C(O)OH, and --C(O)NH.sub.2; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
16. The compound of claim 1, wherein R.sup.5 is selected from
hydrogen, methyl, ethyl, trifluoromethyl, carboxamide, cyano,
piperazinyl, cyclopropyl, phenyl and triazolyl; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
17. The compound of claim 1, wherein the compound is selected from:
TABLE-US-00016 Example Structure 1 ##STR00239## 2 ##STR00240## 3
##STR00241## 4 ##STR00242## 5 ##STR00243## 6 ##STR00244## 7
##STR00245## 8 ##STR00246## 9 ##STR00247## 10 ##STR00248## 11
##STR00249## 12 ##STR00250## 13 ##STR00251## 14 ##STR00252## 15
##STR00253## 16 ##STR00254## 17 ##STR00255## 18 ##STR00256## 19
##STR00257## 20 ##STR00258## 21 ##STR00259## 22 ##STR00260## 23
##STR00261## 24 ##STR00262## 25 ##STR00263## 26 ##STR00264## 27
##STR00265## 28 ##STR00266## 29 ##STR00267## 30 ##STR00268## 31
##STR00269## 32 ##STR00270## 33 ##STR00271## 34 ##STR00272## 35
##STR00273## 36 ##STR00274## 37 ##STR00275## 38 ##STR00276## 39
##STR00277## 40 ##STR00278## 41 ##STR00279## 42 ##STR00280## 43
##STR00281## 44 ##STR00282## 45 ##STR00283## 46 ##STR00284## 47
##STR00285## 48 ##STR00286## 49 ##STR00287## 50 ##STR00288## 51
##STR00289## 52 ##STR00290## 53 ##STR00291## 54 ##STR00292## 55
##STR00293## 56 ##STR00294## 57 ##STR00295## 58 ##STR00296## 59
##STR00297## 60 ##STR00298## 61 ##STR00299## 62 ##STR00300## 63
##STR00301## 64 ##STR00302## 65 ##STR00303## 66 ##STR00304## 67
##STR00305## 68 ##STR00306## 69 ##STR00307## 70 ##STR00308## 71
##STR00309## 72 ##STR00310## 73 ##STR00311## 74 ##STR00312## 75
##STR00313## 76 ##STR00314## 77 ##STR00315## 78 ##STR00316## 79
##STR00317## 80 ##STR00318## 81 ##STR00319## 82 ##STR00320## 83
##STR00321## 84 ##STR00322## 85 ##STR00323## 86 ##STR00324## 87
##STR00325## 88 ##STR00326## 89 ##STR00327## 90 ##STR00328## 91
##STR00329## 92 ##STR00330## 93 ##STR00331## 94 ##STR00332## 95
##STR00333## 96 ##STR00334## 97 ##STR00335## 98 ##STR00336## 99
##STR00337## 100 ##STR00338## 101 ##STR00339## 102 ##STR00340## 103
##STR00341## 104 ##STR00342## 105 ##STR00343## 106 ##STR00344## 107
##STR00345## 108 ##STR00346## 109 ##STR00347## 110 ##STR00348## 111
##STR00349## 112 ##STR00350## 113 ##STR00351## 114 ##STR00352##
or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
18. A pharmaceutical composition comprising the compound according
to claim 1 and at least one pharmaceutically acceptable
vehicle.
19. A method of treating a disease or condition in a human in need
thereof comprising administering to the human a therapeutically
effective amount of the compound or composition according to claim
1, wherein the disease or condition is cancer selected from
prostate cancer, pancreatic cancer, bladder cancer, colorectal
cancer, breast cancer, renal cancer, hepatocellular cancer, lung
cancer, ovarian cancer, cervical cancer, rectum cancer, liver
cancer, kidney cancer, stomach cancer, skin cancer, gastric cancer,
esophageal cancer, head and neck cancer, melanoma, neuroendocrine
cancers, CNS cancers, brain tumors, bone cancer and soft tissue
sarcoma.
20. A method of treating a disease or condition in a human in need
thereof comprising administering to the human a therapeutically
effective amount of the compound or composition according to claim
1, wherein the disease or condition is selected from rheumatoid
arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic
lupus erythematosus, multiple sclerosis, inflammatory bowel
disease, asthma, chronic obstructive airways disease, pneumonitis,
dermatitis, alopecia, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, hepatitis, primary biliary cirrhosis,
sclerosing cholangitis, diabetes, or acute rejection of
transplanted organs.
21. A method of inhibiting the activity of a phosphatidylinositol
3-kinase polypeptide by contacting the polypeptide with the
compound of claim 1.
22. A method of inhibiting excessive or destructive immune
reactions or growth or a proliferation of cancer cells, comprising
administering an effective amount of the compound of claim 1.
23. A composition comprising a compound of claim 1 and a compound
that inhibits or modulates the activity of poly(ADP-ribose)
polymerases (PARP), Tankyrases (TANKs), matrix metalloproteinases
or androgen receptors.
24. A kit comprising the compound of claim 1, a label and/or
instructions for use.
25. A tablet comprising the compound of claim 1 and a
pharmaceutically acceptable carrier.
Description
FIELD
[0001] The present application relates to novel compounds that
selectively inhibit the activities of PI3K isoforms and their uses
in therapeutic treatments.
BACKGROUND
[0002] Cell signaling via 3'-phosphorylated phosphoinositides has
been implicated in a variety of cellular processes, e.g., malignant
transformation, growth factor signaling, inflammation, and immunity
(Rameh et al., J. Biol. Chem., 274:8347-8350, 1999).
Phosphatidylinositol 3-kinase (PI 3-kinase or PI3K) is responsible
for generating these phosphorylated signaling products. PI3K was
initially identified as a protein associated with viral
oncoproteins and growth factor receptor tyrosine kinases that
phosphorylate phosphatidylinositol (PI) and its phosphorylated
derivatives at the 3'-hydroxyl of the inositol ring (Panayotou et
al., Trends Cell Biol., 2:358-60, 1992).
[0003] Three classes of the PI 3-kinase (PI3K) are proposed based
on the substrate specificities. Class I PI3Ks phosphorylate
phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and
phosphatidylinositol-4,5-biphosphate (PIP.sub.2) to produce
phosphatidylinositol-3-phosphate (PIP),
phosphatidylinositol-3,4-biphosphate, and
phosphatidylinositol-3,4,5-triphosphate, respectively. Also, Class
II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, and
Class III PI3Ks phosphorylate PI.
[0004] The initial purification and molecular cloning of PI
3-kinase revealed that it was a heterodimer consisting of p85 and
p110 subunits (Otsu et al., Cell, 65:91-104, 1991; Hiles et al.,
Cell, 70:419-29, 1992). Later, four distinct Class I PI3Ks were
identified and designated as PI3K .alpha., .beta., .delta., and
.gamma. isoforms. Each isoform consists of a distinct 110 kDa
catalytic subunit and a regulatory subunit. The catalytic subunits
of PI3K .alpha., .beta., and .delta. (i.e., p110.alpha.,
p110.beta., and p110.delta., respectively) interacts, individually,
with the same regulatory subunit p85, whereas the catalytic subunit
of PI3K .gamma. (p110.gamma.) interacts with a distinct regulatory
subunit p101.
[0005] Studies have also showed that each PI3K isoform has distinct
expression pattern. For example, PIK3CA which encodes PI3K.alpha.
is frequently mutated in human cancers (Engelman, Nat. Rev. Cancer,
9: 550-562, 2009). Also, PI3K.delta. is generally expressed in
hematopoietic cells. Moreover, PI3K isoforms are shown to be
associated with proliferation or survival signaling in cancers,
inflammatory, or autoimmune diseases. As each PI3K isoform has
different biological function, PI3K isoforms are potential targets
to treat cancer or disorder (U.S. Pat. Nos. 6,800,620; 8,435,988;
8,673,906; US Patent Application Publication No.
US2013/0274253).
[0006] Therefore, there is a need for developing therapeutic agents
that inhibit PI3K isoforms to treat diseases, disorders, or
conditions that are mediated by PI3K.
SUMMARY
[0007] The present application provides novel compounds that are
inhibitors of PI3K isoforms. The application also provides
compositions, including pharmaceutical compositions, kits that
include the compounds, and methods of using and making the
compounds. The compounds provided herein are useful in treating
diseases, disorders, or conditions that are mediated by PI3K
isoforms. The application also provides compounds for use in
therapy. The application further provides compounds for use in a
method of treating a disease, disorder, or condition that is
mediated by PI3K isoforms. Moreover, the application provides uses
of the compounds in the manufacture of a medicament for the
treatment of a disease, disorder or condition that is mediated by
PI3K isoforms. In typical embodiments, provided are compounds of
formula I:
##STR00002## [0008] wherein n is 1, 2, 3 or 4; [0009] s is 1 or 2;
[0010] t is 1 or 2; [0011] each R.sup.1 is independently selected
from hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0012] wherein
each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and
4-10 membered heterocyclyl is optionally substituted with one to
four R.sup.100; [0013] R.sup.2 is selected from hydrogen, halo,
cyano, hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0014] wherein
each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and
4-10 membered heterocyclyl is optionally substituted with one to
four R.sup.101; [0015] R.sup.3 is selected from hydrogen, halo,
cyano, hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--N(R.sup.a)C(O)NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0016] wherein
each wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl and 4-10 membered heterocyclyl is optionally substituted
with one to four R.sup.102; [0017] R.sup.4 is a 5-10 membered
heteroaryl; [0018] wherein said 5-10 membered heteroaryl is
optionally substituted with one to four R.sup.103; [0019] each
R.sup.5 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b,
--N(R.sup.a)C(O)NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2R.sup.a,
--OR.sup.a, --SR.sup.b, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl containing 1 to 4 heteroatoms selected from the
group consisting of N, O, and S, and 4-10 membered heterocyclyl
containing 1 to 4 heteroatoms selected from the group consisting of
N, O, and S; [0020] wherein each C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl and 4-10 membered heterocyclyl is
optionally substituted with one to four R.sup.104; [0021] each
R.sup.6 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; [0022]
each R.sup.a and R.sup.b is independently selected from hydrogen,
C.sub.6-10 aryl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6
alkynyl; [0023] wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, is optionally substituted with one to four
R.sup.200; [0024] each R.sup.100, R.sup.101, R.sup.102, R.sup.103
and R.sup.104 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, oxo, thioxo, vinyl, --C(O)R.sup.c, --C(O)OR.sup.c,
--C(O)NR.sup.cR.sup.d, --N(R.sup.c)C(O)R.sup.d,
--N(R.sup.a)C(O)NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2R.sup.a,
--S(O)NR.sup.cR.sup.d, --S(O).sub.2NR.sup.cR.sup.d, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.cR.sup.d, --OR.sup.c, --SR.sup.d,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10
membered heterocyclyl; [0025] wherein each C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10 membered
heterocyclyl is optionally substituted with one to four R.sup.201;
[0026] each R.sup.c and R.sup.d is independently selected from
hydrogen, C.sub.6-10 aryl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl; [0027] each R.sup.200 and R.sup.201 is
independently selected from hydrogen, halo, cyano, hydroxy, amino,
oxo, thioxo, vinyl, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --N(R.sup.e)C(O)R.sup.f,
--S(O)NR.sup.eR.sup.f, --S(O).sub.2NR.sup.eR.sup.f, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --N(R.sup.a)C(O)NR.sup.aR.sup.b,
--OC(O)NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2R.sup.a, --NR.sup.eR.sup.f, --OR.sup.e,
--SR.sup.e, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6
alkynyl; [0028] each R.sup.e and R.sup.f is independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6
alkynyl; [0029] each R.sup.g is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0030] wherein
each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and
4-10 membered heterocyclyl is optionally substituted with one to
four R.sup.200; [0031] or a pharmaceutically acceptable salt,
isomer, or a mixture thereof.
[0032] In certain embodiments, the PI3K inhibitors are the
compounds selected from Table 1, a pharmaceutically acceptable
salt, isomer, or a mixture thereof. In additional embodiments, the
compound is an (S)-enantiomer. In other embodiments, the compound
is an (R)-enantiomer. In other additional embodiments, the compound
is an atropisomer. The application also provides a pharmaceutical
composition that comprises a compound of formula (I), a
pharmaceutically acceptable salt, isomer, or a mixture thereof,
together with at least one pharmaceutically acceptable vehicle.
Examples of a pharmaceutically acceptable vehicle may be selected
from carriers, adjuvants, and excipients.
[0033] Further provided herein is a method of treating a disease,
disorder, or condition in a human in need thereof by administering
to the human a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt, isomer, or a
mixture thereof. Further provided is a compound of formula (I) for
use in a method of treating a disease, disorder or condition that
is mediated by PI3K isoforms. The application also provides the use
of a compound of formula (I) in the manufacture of a medicament for
the treatment of a disease, disorder or condition that is mediated
by PI3K isoforms. In certain embodiments, the disease, disorder, or
condition is associated or mediated by PI3K. In some embodiments,
the disease, disorder, or condition is an inflammatory disorder. In
other embodiments, the disease, disorder, or condition is a
cancer.
[0034] Also provided herein is a method of inhibiting the activity
of a phosphatidylinositol 3-kinase polypeptide by contacting the
polypeptide with a compound of formula (I) or a pharmaceutically
acceptable salt, isomer, or a mixture thereof.
[0035] Further provided is a method of inhibiting excessive or
destructive immune reactions, comprising administering an effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt, isomer, or a mixture thereof.
[0036] Also provided is a method of inhibiting growth or
proliferation of cancer cells comprising contacting the cancer
cells with an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0037] Also provided is a kit that includes a compound of formula
(I) or a pharmaceutically acceptable salt, isomer, or a mixture
thereof. The kit may further comprise a label and/or instructions
for use of the compound in treating a disease, disorder, or
condition in a human in need thereof. In some embodiments, the
disease, disorder, or condition may be associated or mediated by
PI3K activity.
[0038] Also provided are articles of manufacture that include a
compound of formula (I) or a pharmaceutically acceptable salt,
isomer, or a mixture thereof, and a container. In one embodiment,
the container may be a vial, jar, ampoule, preloaded syringe, or an
intravenous bag.
DETAILED DESCRIPTION
[0039] The following description sets forth exemplary methods,
parameters and the like. Such description is not intended as a
limitation on the scope of the present application but is instead
provided as exemplary embodiments.
[0040] As used herein, the following words, phrases and symbols are
generally intended to have the meanings as set forth below, except
to the extent that the context in which they are used indicates
otherwise.
[0041] A dash ("--") that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --CONH.sub.2 is attached through the carbon atom. A dash
at the front or end of a chemical group is a matter of convenience;
chemical groups may be depicted with or without one or more dashes
without losing their ordinary meaning. A wavy line drawn through a
line in a structure indicates a point of attachment of a group.
Unless chemically or structurally required, no directionality is
indicated or implied by the order in which a chemical group is
written or named.
[0042] The prefix "C.sub.u-v" indicates that the following group
has from u to v carbon atoms. For example, "C.sub.1-6 alkyl"
indicates that the alkyl group has from 1 to 6 carbon atoms.
[0043] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. In certain embodiments, the term "about" includes
the indicated amount .+-.10%. In other embodiments, the term
"about" includes the indicated amount .+-.5%. In certain other
embodiments, the term "about" includes the indicated amount .+-.1%.
Also, to the term "about X" includes description of "X". Also, the
singular forms "a" and "the" include plural references unless the
context clearly dictates otherwise. Thus, e.g., reference to "the
compound" includes a plurality of such compounds and reference to
"the assay" includes reference to one or more assays and
equivalents thereof known to those skilled in the art.
[0044] "Alkyl" refers to an unbranched or branched saturated
hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms
(i.e., 1-20 alkyl), 1 to 8 carbon atoms (i.e., C.sub.1-8 alkyl), 1
to 6 carbon atoms (i.e., C.sub.1-6 alkyl), or 1 to 4 carbon atoms
(i.e., C.sub.1-4 alkyl). Examples of alkyl groups include methyl,
ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,
3-hexyl, and 3-methylpentyl. When an alkyl residue having a
specific number of carbons is named, all geometric isomers having
that number of carbons may be encompassed; thus, for example,
"butyl" includes n-butyl, sec-butyl, isobutyl and t-butyl; "propyl"
includes n-propyl and isopropyl.
[0045] "Alkenyl" refers to an aliphatic group containing at least
one carbon-carbon double bond and having from 2 to 20 carbon atoms
(i.e., C.sub.2-20 alkenyl), 2 to 8 carbon atoms (i.e., C.sub.2-8
alkenyl), 2 to 6 carbon atoms (i.e., C.sub.2-6 alkenyl), or 2 to 4
carbon atoms (i.e., C.sub.2-4 alkenyl). Examples of alkenyl groups
include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and
1,3-butadienyl).
[0046] "Alkynyl" refers to an aliphatic group containing at least
one carbon-carbon triple bond and having from 2 to 20 carbon atoms
(i.e., C.sub.2-20 alkynyl), 2 to 8 carbon atoms (i.e., C.sub.2-8
alkynyl), 2 to 6 carbon atoms (i.e., C.sub.2-6 alkynyl), or 2 to 4
carbon atoms (i.e., C.sub.2-4 alkynyl). The term "alkynyl" also
includes those groups having one triple bond and one double
bond.
[0047] "Alkoxy" refers to the group "alkyl-O--". Examples of alkoxy
groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and
1,2-dimethylbutoxy.
[0048] "Acyl" refers to a group --C(.dbd.O)R, wherein R is
hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl,
or heteroaryl; each of which may be optionally substituted, as
defined herein. Examples of acyl include formyl, acetyl,
cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
[0049] "Amido" refers to both a "C-amido" group which refers to the
group --C(.dbd.O)NR.sup.yR.sup.z and an "N-amido" group which
refers to the group --NR.sup.yC(.dbd.O)R.sup.z, wherein R.sup.y and
R.sup.z are independently selected from the group consisting of
hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may
be optionally substituted.
[0050] "Amino" refers to the group --NR.sup.yR.sup.z wherein
R.sup.y and R.sup.z are independently selected from the group
consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each
of which may be optionally substituted.
[0051] "Aryl" refers to an aromatic carbocyclic group having a
single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or
tricyclic) including fused systems. As used herein, aryl has 6 to
20 ring carbon atoms (i.e., C.sub.6-20 aryl), 6 to 12 carbon ring
atoms (i.e., C.sub.6-12 aryl), or 6 to 10 carbon ring atoms (i.e.,
C.sub.6-10 aryl). Examples of aryl groups include phenyl, naphthyl,
fluorenyl, and anthryl. Aryl, however, does not encompass or
overlap in any way with heteroaryl defined below. If one or more
aryl groups are fused with a heteroaryl ring, the resulting ring
system is heteroaryl.
[0052] "Cyano" or "carbonitrile" refers to the group --CN.
[0053] "Cycloalkyl" refers to a saturated or partially saturated
cyclic alkyl group having a single ring or multiple rings including
fused, bridged, and spiro ring systems. The term "cycloalkyl"
includes cycloalkenyl groups (i.e. the cyclic group having at least
one alkenyl). As used herein, cycloalkyl has from 3 to 20 ring
carbon atoms ((i.e., C.sub.3-20 cycloalkyl), 3 to 12 ring carbon
atoms (i.e., C.sub.1-12 cycloalkyl), 3 to 10 ring carbon atoms
(i.e., C.sub.3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e.,
C.sub.3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C.sub.3-6
cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl.
[0054] "Halogen" or "halo" includes fluoro, chloro, bromo, and
iodo. "Haloalkyl" refers to an unbranched or branched alkyl group
as defined above, wherein one or more hydrogen atoms are replaced
by a halogen. For example, where a residue is substituted with more
than one halogen, it may be referred to by using a prefix
corresponding to the number of halogen moieties attached.
Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two
("di") or three ("tri") halo groups, which may be, but are not
necessarily, the same halogen. Examples of haloalkyl include
difluoromethyl (--CHF.sub.2) and trifluoromethyl (--CF.sub.3).
[0055] "Heteroalkyl" refers to an alkyl group in which one or more
of the carbon atoms (and any associated hydrogen atoms) are each
independently replaced with the same or different heteroatomic
group. By way of example, 1, 2 or 3 carbon atoms may be
independently replaced with the same or different heteroatomic
group. Heteroatomic groups include, but are not limited to, --NR--,
--O--, --S--, --S(O)--, --S(O).sub.2--, and the like, where R is H,
alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or
heterocycloalkyl, each of which may be optionally substituted.
Examples of heteroalkyl groups include --OCH.sub.3,
--CH.sub.2OCH.sub.3, --SCH.sub.3, --CH.sub.2SCH.sub.3,
--NRCH.sub.3, and --CH.sub.2NRCH.sub.3, where R is hydrogen, alkyl,
aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be
optionally substituted. As used herein, heteroalkyl include 1 to 10
carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to
3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
[0056] "Heteroaryl" refers to an aromatic group having a single
ring, multiple rings, or multiple fused rings, with one or more
ring heteroatoms independently selected from nitrogen, oxygen, and
sulfur. As used herein, heteroaryl include 1 to 20 ring carbon
atoms, 3 to 12 ring carbon atoms, or 3 to 8 carbon ring atoms; and
1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1
to 2 ring heteroatoms, or 1 ring heteroatom independently selected
from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups
include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl,
and pyrazolyl. Heteroaryl does not encompass or overlap with aryl
as defined above.
[0057] "Heterocycloalkyl" refers to a saturated or unsaturated
cyclic alkyl group, with one or more ring heteroatoms independently
selected from nitrogen, oxygen and sulfur. The term
"heterocycloalkyl" includes heterocycloalkenyl groups (i.e. the
heterocycloalkyl group having at least one alkenyl). A
heterocycloalkyl may be a single ring or multiple rings wherein the
multiple rings may be fused, bridged, or spiro. As used herein,
heterocycloalkyl has 2 to 20 ring carbon atoms, 2 to 12 ring carbon
atoms, 2 to 10 ring carbon atoms, 2 to 8 ring carbon atoms, 3 to 12
ring carbon atoms, 3 to 8 ring carbon atoms, or 3 to 6 ring carbon
atoms; and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3
ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom
independently selected from nitrogen, sulfur or oxygen. Examples of
heterocycloalkyl groups include pyrrolidinyl, piperidinyl,
piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
[0058] "Hydroxy" or "hydroxyl" refers to the group --OH.
[0059] "Oxo" refers to the group (.dbd.O) or (O).
[0060] "Sulfonyl" refers to the group --S(O).sub.2R, where R is
alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or
aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl,
phenylsulfonyl, and toluenesulfonyl.
[0061] Certain commonly used alternative chemical names may be
used. For example, a divalent group such as a divalent "alkyl"
group, a divalent "aryl" group, etc., may also be referred to as an
"alkylene" group or an "alkylenyl" group, an "arylene" group or an
"arylenyl" group, respectively. Also, unless indicated explicitly
otherwise, where combinations of groups are referred to herein as
one moiety, e.g. arylalkyl, the last mentioned group contains the
atom by which the moiety is attached to the rest of the
molecule.
[0062] The terms "optional" or "optionally" means that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances where said event or
circumstance occurs and instances in which it does not. Also, the
term "optionally substituted" refers to any one or more hydrogen
atoms on the designated atom or group may or may not be replaced by
a moiety other than hydrogen.
[0063] The term "substituted" means that any one or more hydrogen
atoms on the designated atom or group is replaced with one or more
substituents other than hydrogen, provided that the designated
atom's normal valence is not exceeded. The one or more substituents
include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy,
acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl,
carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl,
heteroaryl, heterocycloalkyl, hydroxy, hydrazino, imino, oxo,
nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate,
thiol, thione, or combinations thereof. By way of example, there
may be one, two, three, four, five, or six substituents. Polymers
or similar indefinite structures arrived at by defining
substituents with further substituents appended ad infinitum (e.g.,
a substituted aryl having a substituted alkyl which is itself
substituted with a substituted aryl group, which is further
substituted by a substituted heteroalkyl group, etc.) are not
intended for inclusion herein. Unless otherwise noted, the maximum
number of serial substitutions in compounds described herein is
three. For example, serial substitutions of substituted aryl groups
with two other substituted aryl groups are limited to substituted
aryl (substituted aryl) substituted aryl. Similarly, the above
definitions are not intended to include impermissible substitution
patterns (e.g., methyl substituted with 5 fluorines or heteroaryl
groups having two adjacent oxygen ring atoms). Such impermissible
substitution patterns are well known to the skilled artisan. When
used to modify a chemical group, the term "substituted" may
describe other chemical groups defined herein. For example, the
term "substituted aryl" includes, but is not limited to,
"alkylaryl." Unless specified otherwise, where a group is described
as optionally substituted, any substituents of the group are
themselves unsubstituted.
[0064] In some embodiments, the term "substituted alkyl" refers to
an alkyl group having one or more substituents including hydroxyl,
halo, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
In additional embodiments, "substituted cycloalkyl" refers to a
cycloalkyl group having one or more substituents including alkyl,
haloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, halo,
hydroxyl; "substituted aryl" refers to an aryl group having one or
more substituents including halo, alkyl, haloalkyl,
heterocycloalkyl, heteroaryl, alkoxy, and cyano, and "substituted
sulfonyl" refers to a group --S(O).sub.2R, in which R is
substituted with one or more substituents of alkyl, cycloalkyl,
heterocycloalkyl, aryl or heteroaryl. In other embodiments, the one
or more substituents may be further substituted with halo, alkyl,
haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl, each of which is substituted. In other embodiments, the
substituents may be further substituted with halo, alkyl,
haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl, each of which is unsubstituted.
[0065] Compounds of the invention are named using Chembiodraw Ultra
(version 14).
TABLE-US-00001 List of Abbreviations and Acronyms Abbreviation
Meaning .degree. C. Degree Celsius Ac Acetyl aq. Aqueous ATP
Adenosine triphosphate br Broad BSA Bovine serum albumin Cbz
Carboxybenzyl COD Cyclooctadiene COPD Chronic obstructive pulmonary
disease d Doublet DCE Dichloroethene DCM Dichloromethane dd Doublet
of doublets DIEA Diisopropylethylamine DMF Dimethylformamide DMSO
Dimethylsulfoxide dt Doublet-triplet DTT Dithiothreitol EC.sub.50
The half maximal effective concentration eq Equivalents ES/MS
Electrospray mass spectrometry Et Ethyl FBS Fetal bovine serum g
Grams HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid
HPLC High pressure liquid chromatography hr or h or hrs Hours Hz
Hertz IBD Inflammatory bowel disease i-pr Isopropyl J Coupling
constant (MHz) Kg/kg Kilogram LCMS Liquid chromatography-mass
spectrometry LPS Lipopolysaccharide M Molar m multiplet M+ Mass
peak M + H+ Mass peak plus hydrogen Me Methyl mg Milligram MHz
Megahertz ml/mL Milliliter mM Millimolar mmol Millimole MOPS
3-Morpholinopropane-1-sulfonic acid MS Mass spectroscopy Ms
methanesulfonyl nBu/Bu Butyl nL Nanoliter nm Nanometer NMR Nuclear
magnetic resonance NMP N-methylpyrrolidinone NP-40 Nonyl
phenoxypolyethoxylethanol Pd--C/Pd/C Palladium on Carbon Ph Phenyl
q Quartet q.s. Quantity sufficient to achieve a stated function RP
Reverse phase rt Room temperature s Singlet sat. Saturated T
Triplet TEA Triethylamine Tf Trifluoromethanesulfonyl TFA
Trifluoroacetic acid THF Tetrahydrofuran TR-FRET Time-resolved
fluorescence energy transfer .delta. Chemical shift (ppm)
.mu.L/.mu.l Microliter .mu.M Micromolar
Compounds
[0066] The present application provides compounds that function as
inhibitors of PI3K isoforms. In one aspect, provided are the
compounds having the structure of Formula I:
##STR00003## [0067] wherein n is 1, 2, 3 or 4; [0068] s is 1 or 2;
[0069] t is 1 or 2; [0070] each R.sup.1 is independently selected
from hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0071] wherein
each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and
4-10 membered heterocyclyl is optionally substituted with one to
four R.sup.100; [0072] R.sup.2 is selected from hydrogen, halo,
cyano, hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0073] wherein
each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and
4-10 membered heterocyclyl is optionally substituted with one to
four R.sup.101; [0074] R.sup.3 is selected from hydrogen, halo,
cyano, hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--N(R.sup.a)C(O)NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0075] wherein
each wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl and 4-10 membered heterocyclyl is optionally substituted
with one to four R.sup.102; [0076] R.sup.4 is a 5-10 membered
heteroaryl; [0077] wherein said 5-10 membered heteroaryl is
optionally substituted with one to four R.sup.103; [0078] each
R.sup.5 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--N(R.sup.a)C(O)NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0079] wherein
each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and
4-10 membered heterocyclyl is optionally substituted with one to
four R.sup.104; [0080] each R.sup.6 is independently selected from
hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; [0081]
each R.sup.a and R.sup.b is independently selected from hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; [0082]
wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
is optionally substituted with one to four R.sup.200; [0083] each
R.sup.100, R.sup.101, R.sup.102, R.sup.103 and R.sup.104 is
independently selected from hydrogen, halo, cyano, hydroxy, amino,
oxo, thioxo, vinyl, --C(O)R.sup.c, --C(O)OR.sup.c,
--C(O)NR.sup.cR.sup.d, --N(R.sup.c)C(O)R.sup.d,
--N(R.sup.a)C(O)NR.sup.aR.sup.b, --OC(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --NR.sup.aS(O).sub.2R.sup.a,
--S(O)NR.sup.cR.sup.d, --S(O).sub.2NR.sup.cR.sup.d, --S(O)R.sup.c,
--S(O).sub.2R.sup.c, --NR.sup.cR.sup.d, --OR.sup.c, --SR.sup.d,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10
membered heterocyclyl; [0084] wherein each C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10 membered
heterocyclyl is optionally substituted with one to four R.sup.201;
[0085] each R.sup.c and R.sup.d is independently selected from
hydrogen, C.sub.6-10 aryl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl; [0086] each R.sup.200 and R.sup.201 is
independently selected from hydrogen, halo, cyano, hydroxy, amino,
oxo, thioxo, vinyl, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --N(R.sup.e)C(O)R.sup.f,
--S(O)NR.sup.eR.sup.f, --S(O).sub.2NR.sup.eR.sup.f, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --NR.sup.eR.sup.f, --OR.sup.e, --SR.sup.e,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; [0087]
each R.sup.e and R.sup.f is independently selected from hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; [0088]
each R.sup.g is independently selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S, and
4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S; [0089] wherein each
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-10
membered heterocyclyl is optionally substituted with one to four
R.sup.200; [0090] or a pharmaceutically acceptable salt, isomer, or
a mixture thereof.
[0091] In another aspect, provided are compounds of Formula IA:
##STR00004## [0092] wherein n, s, t, R.sup.1, R.sup.2, R.sup.4,
R.sup.5 and R.sup.6 are as defined above; [0093] X.sup.1 is N or C;
[0094] each X.sup.2, X.sup.3, X.sup.4 and X.sup.5 is independently
selected from S, O, CR.sup.10 and NR.sup.11; [0095] wherein each
R.sup.10 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0096] wherein
each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-8 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and
4-10 membered heterocyclyl is optionally substituted with one to
four R.sup.104; [0097] wherein each R.sup.11 is independently
selected from absent, hydrogen, halo, cyano, hydroxy, amino,
--C(O)R.sup.a, --C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b,
--N(R.sup.a)C(O)R.sup.b, --S(O)NR.sup.aR.sup.b,
--S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g, --S(O).sub.2R.sup.g,
--NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S, and
4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S; [0098] alternatively, one
R.sup.10 and one R.sup.11 group, together with the atoms to which
they are attached form a five, six or seven membered fused, or
bridged ring; [0099] or a pharmaceutically acceptable salt, isomer,
or a mixture thereof.
[0100] In another aspect, provided are compounds of Formula IB:
##STR00005## [0101] wherein n, s, t, R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are as defined above; [0102] each R.sup.13 is independently
selected from hydrogen, halo, cyano, hydroxy, amino, --C(O)R.sup.a,
--C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8
cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1
to 4 heteroatoms selected from the group consisting of N, O, and S,
and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms
selected from the group consisting of N, O, and S; [0103] each
R.sup.a and R.sup.b is independently selected from hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; [0104]
wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
is optionally substituted with one to four R.sup.200; [0105] each
R.sup.200 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, oxo, thioxo, vinyl, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --N(R.sup.e)C(O)R.sup.f,
--S(O)NR.sup.eR.sup.f, --S(O).sub.2NR.sup.eR.sup.f, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --NR.sup.eR.sup.f, --OR.sup.e, --SR.sup.e,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; [0106]
each R.sup.e and R.sup.f is independently selected from hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; [0107] or
a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0108] In another aspect, provided are compounds of Formula IC:
##STR00006## [0109] wherein n, s, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, and R.sup.13 are as defined above; [0110] or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0111] In another aspect, provided are compounds of Formula ID:
##STR00007## [0112] wherein n, s, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, X.sup.1, X.sup.2, X.sup.3, X.sup.4 and X.sup.5 are as
defined above; [0113] or a pharmaceutically acceptable salt,
isomer, or a mixture thereof.
[0114] In another aspect, provided are compounds of Formula IE:
##STR00008## [0115] wherein n, s, t, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, and R.sup.13 are as defined above; [0116] or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0117] In another aspect, provided are compounds of Formula IF:
##STR00009## [0118] wherein n, s, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, and R.sup.13 are as defined above; [0119] or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0120] In another aspect, provided are compounds of Formula IG:
##STR00010## [0121] wherein n, s, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, X.sup.1, X.sup.2, X.sup.3, X.sup.4 and X.sup.5 are as
defined above; [0122] or a pharmaceutically acceptable salt,
isomer, or a mixture thereof.
[0123] In another aspect, provided are compounds of Formula IH:
##STR00011## [0124] wherein n, s, t, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, and R.sup.13 are as defined above; [0125] or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0126] In another aspect, provided are compounds of Formula IJ:
##STR00012## [0127] wherein n, s, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, and R.sup.13 are as defined above; [0128] or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0129] In another aspect, provided are compounds of Formula
(IK):
##STR00013## [0130] wherein n, s, R.sup.1, R.sup.2, R.sup.5, and
R.sup.13 are as defined above; [0131] m is 1, 2 or 3; [0132] each
R.sup.14 is independently selected from hydrogen, halo, cyano,
hydroxy, amino, --C(O)R.sup.a, --C(O)OR.sup.b,
--C(O)NR.sup.aR.sup.b, --N(R.sup.a)C(O)R.sup.b,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g,
--S(O).sub.2R.sup.g, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.3-8
cycloalkyl; [0133] each R.sup.a and R.sup.b is independently
selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl; [0134] wherein each C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, is optionally substituted with one to
four R.sup.200; [0135] each R.sup.200 is independently selected
from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl,
--C(O)R.sup.e, --C(O)OR.sup.e, --C(O)NR.sup.eR.sup.f,
--N(R.sup.e)C(O)R.sup.f, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --S(O)R.sup.g, --S(O).sub.2R.sup.g,
--NR.sup.eR.sup.f, --OR.sup.e, --SR.sup.e, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; [0136] each R.sup.e and
R.sup.f is independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; [0137] or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0138] In another aspect, provided are compounds of Formula IL:
##STR00014## [0139] wherein n, m, s, R.sup.1, R.sup.2, R.sup.4,
R.sup.5, R.sup.13 and R.sup.14 are as defined above; [0140] or a
pharmaceutically acceptable salt thereof.
[0141] In certain embodiments, provided is a compound of Formula I,
wherein R.sup.3 is
##STR00015## [0142] wherein t is 1 or 2; [0143] each R.sup.13 is
independently selected from hydrogen, halo, cyano, hydroxy, amino,
--C(O)R.sup.a, --C(O)OR.sup.b, --C(O)NR.sup.aR.sup.b,
--N(R.sup.a)C(O)R.sup.b, --S(O)NR.sup.aR.sup.b,
--S(O).sub.2NR.sup.aR.sup.b, --S(O)R.sup.g, --S(O).sub.2R.sup.g,
--NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.b, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S, and
4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S; [0144] or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0145] In certain embodiments, provided is a compound of Formula ID
or IG, or a pharmaceutically acceptable salt, isomer, or a mixture
thereof; wherein the substituent
##STR00016##
is selected from:
##STR00017##
[0146] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ or IK, wherein R.sup.4 is
selected from:
##STR00018##
[0147] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.1 is
selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl,
propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl,
fluoroethyl, difluoroethyl and trifluoroethyl; or a
pharmaceutically acceptable salt, isomer, or a mixture thereof.
[0148] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.1 is
fluoro or chloro; or a pharmaceutically acceptable salt, isomer, or
a mixture thereof.
[0149] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.1 is
fluoro and n is 2.
[0150] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.2 is
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 5-6 membered heteroaryl
containing 1 to 3 heteroatoms selected from the group consisting of
N, O, and S, and 4-6 membered heterocyclyl containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S;
wherein each C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 5-6 membered
heteroaryl and 4-6 membered heterocyclyl is optionally substituted
with one to four R.sup.101; or a pharmaceutically acceptable salt,
isomer, or a mixture thereof.
[0151] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.2 is
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, or 4-6 membered heterocyclyl
containing 1 heteroatom selected from the group consisting of N, O,
and S; or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0152] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.2 is
selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, t-butyl, furanyl, tetrahydrofuranyl, oxetanyl, and
cyclopropyl; or a pharmaceutically acceptable salt, isomer, or a
mixture thereof.
[0153] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.5 is
selected from hydrogen, methyl, ethyl, trifluoromethyl,
carboxamide, cyano, piperazinyl, cyclopropyl, phenyl and triazolyl;
or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0154] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.5 is
selected from hydrogen or methyl.
[0155] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R.sup.1 is
selected from hydrogen, Cl, F and methyl, or a pharmaceutically
acceptable salt thereof.
[0156] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, or IL, wherein R.sup.2 is
selected from hydrogen or a substituent selected from the table
below:
##STR00019##
or a pharmaceutically acceptable salt thereof.
[0157] In certain embodiments, provided is a compound of Formula I,
wherein R.sup.3 is selected from hydrogen or a substituent selected
from --C(O)OH, --C(O)NH.sub.2
##STR00020##
or a pharmaceutically acceptable salt thereof.
[0158] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH or IJ, wherein R.sup.4 is a 5-10
membered heteroaryl having one or two nitrogens, optionally
substituted with one to four R.sup.103.
[0159] In certain embodiments, R.sup.103 is selected from cyano,
amino, halo, and C.sub.1-6 alkyl.
[0160] In certain embodiments, provided is a compound of Formula I,
IA, IB, IC, ID, IE, IF, IG, IH or IJ, wherein R.sup.4 is selected
from hydrogen or a substituent selected from the table below:
##STR00021##
or a pharmaceutically acceptable salt thereof.
[0161] In certain embodiments, provided is a compound selected from
Table 1, or a pharmaceutically acceptable salt, isomer, or a
mixture thereof:
TABLE-US-00002 TABLE 1 Example Structure 1 ##STR00022## 2
##STR00023## 3 ##STR00024## 4 ##STR00025## 5 ##STR00026## 6
##STR00027## 7 ##STR00028## 8 ##STR00029## 9 ##STR00030## 10
##STR00031## 11 ##STR00032## 12 ##STR00033## 13 ##STR00034## 14
##STR00035## 15 ##STR00036## 16 ##STR00037## 17 ##STR00038## 18
##STR00039## 19 ##STR00040## 20 ##STR00041## 21 ##STR00042## 22
##STR00043## 23 ##STR00044## 24 ##STR00045## 25 ##STR00046## 26
##STR00047## 27 ##STR00048## 28 ##STR00049## 29 ##STR00050## 30
##STR00051## 31 ##STR00052## 32 ##STR00053## 33 ##STR00054## 34
##STR00055## 35 ##STR00056## 36 ##STR00057## 37 ##STR00058## 38
##STR00059## 39 ##STR00060## 40 ##STR00061## 41 ##STR00062## 42
##STR00063## 43 ##STR00064## 44 ##STR00065## 45 ##STR00066## 46
##STR00067## 47 ##STR00068## 48 ##STR00069## 49 ##STR00070## 50
##STR00071## 51 ##STR00072## 52 ##STR00073## 53 ##STR00074## 54
##STR00075## 55 ##STR00076## 56 ##STR00077## 57 ##STR00078## 58
##STR00079## 59 ##STR00080## 60 ##STR00081## 61 ##STR00082## 62
##STR00083## 63 ##STR00084## 64 ##STR00085## 65 ##STR00086## 66
##STR00087## 67 ##STR00088## 68 ##STR00089## 69 ##STR00090## 70
##STR00091## 71 ##STR00092## 72 ##STR00093## 73 ##STR00094## 74
##STR00095## 75 ##STR00096## 76 ##STR00097## 77 ##STR00098## 78
##STR00099## 79 ##STR00100## 80 ##STR00101## 81 ##STR00102## 82
##STR00103## 83 ##STR00104## 84 ##STR00105## 85 ##STR00106## 86
##STR00107## 87 ##STR00108## 88 ##STR00109## 89 ##STR00110## 90
##STR00111## 91 ##STR00112## 92 ##STR00113## 93 ##STR00114## 94
##STR00115## 95 ##STR00116## 96 ##STR00117## 97 ##STR00118## 98
##STR00119## 99 ##STR00120## 100 ##STR00121## 101 ##STR00122## 102
##STR00123## 103 ##STR00124## 104 ##STR00125## 105 ##STR00126## 106
##STR00127## 107 ##STR00128## 108 ##STR00129## 109 ##STR00130## 110
##STR00131## 111 ##STR00132## 112 ##STR00133## 113 ##STR00134## 114
##STR00135## 115 ##STR00136## 116 ##STR00137## 117 ##STR00138## 118
##STR00139## 119 ##STR00140## 120 ##STR00141## 121 ##STR00142## 122
##STR00143## 123 ##STR00144##
124 ##STR00145## 125 ##STR00146## 126 ##STR00147## 127 ##STR00148##
128 ##STR00149## 129 ##STR00150## 130 ##STR00151## 131 ##STR00152##
132 ##STR00153## 133 ##STR00154## 134 ##STR00155## 135 ##STR00156##
136 ##STR00157## 137 ##STR00158## 138 ##STR00159## 139 ##STR00160##
140 ##STR00161## 141 ##STR00162## 142 ##STR00163## 143 ##STR00164##
144 ##STR00165## 145 ##STR00166## 146 ##STR00167## 147 ##STR00168##
148 ##STR00169## 149 ##STR00170## 150 ##STR00171## 151 ##STR00172##
152 ##STR00173## 153 ##STR00174## 154 ##STR00175## 155 ##STR00176##
156 ##STR00177## 157 ##STR00178## 158 ##STR00179## 159 ##STR00180##
160 ##STR00181## 161 ##STR00182## 162 ##STR00183## 163 ##STR00184##
164 ##STR00185## 165 ##STR00186## 166 ##STR00187## 167
##STR00188##
[0162] The present application provides pharmaceutically acceptable
salts, hydrates, solvates, isomers, tautomers, stereoisomers,
enantiomers, racemates, atropisomers, polymorphs, prodrugs, or a
mixture thereof, of the compounds described herein. The terms "a
compound of the present application," "a compound described
herein," "a compound of any of the formulae described herein," or
variant thereof refer to a compound having the structure of any of
the formulae, I, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL. In
some embodiments, compounds of the present application are
Compounds 1-114 as described herein.
[0163] "Pharmaceutically acceptable" or "physiologically
acceptable" refer to compounds, salts, compositions, dosage forms
and other materials which are useful in preparing a pharmaceutical
composition that is suitable for veterinary or human pharmaceutical
use. "Pharmaceutically acceptable salts" or "physiologically
acceptable salts" refer to salts of pharmaceutical compounds that
retain the biological effectiveness and properties of the
underlying compound, and which are not biologically or otherwise
undesirable. There are acid addition salts and base addition salts.
Pharmaceutically acceptable acid addition salts may be prepared
from inorganic and organic acids. Acids and bases useful for
reaction with an underlying compound to form pharmaceutically
acceptable salts (acid addition or base addition salts
respectively) are known to one of skill in the art. Similarly,
methods of preparing pharmaceutically acceptable salts from an
underlying compound (upon disclosure) are known to one of skill in
the art and are disclosed in for example, Berge, at al. Journal of
Pharmaceutical Science, January 1977 vol. 66, No. 1, and other
sources. If the compounds described herein are obtained as an acid
addition salt, the free base can be obtained by basifying a
solution of the acid salt. Conversely, if the product is a free
base, an addition salt, particularly a pharmaceutically acceptable
addition salt, may be produced by dissolving the free base in a
suitable organic solvent and treating the solution with an acid, in
accordance with conventional procedures for preparing acid addition
salts from base compounds. Salts derived from organic acids include
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluene-sulfonic acid, salicylic acid, and the like. Salts
derived from mineral acids include, hydrochloride, hydrobromide,
hydroiodide, nitrate, phosphate, and sulfate. Likewise,
pharmaceutically acceptable base addition salts can be prepared
from inorganic and organic bases. Salts derived from inorganic
bases include, by way of example only, sodium, potassium, lithium,
ammonium, calcium and magnesium salts. Salts derived from organic
bases include, but are not limited to, salts of primary, secondary
and tertiary amines, such as alkyl amines (i.e., NH.sub.2(alkyl)),
dialkyl amines (i.e., HN(alkyl).sub.2), trialkyl amines (i.e.,
N(alkyl).sub.3), substituted alkyl amines (i.e.,
NH.sub.2(substituted alkyl)), di(substituted alkyl) amines (i.e.,
HN(substituted alkyl).sub.2), tri(substituted alkyl) amines (i.e.,
N(substituted alkyl).sub.3), alkenyl amines (i.e.,
NH.sub.2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl).sub.2),
trialkenyl amines (i.e., N(alkenyl).sub.3), substituted alkenyl
amines (i.e., NH.sub.2(substituted alkenyl)), di(substituted
alkenyl) amines (i.e., HN(substituted alkenyl).sub.2),
tri(substituted alkenyl) amines (i.e., N(substituted
alkenyl).sub.3, mono-, di- or tri-cycloalkyl amines (i.e.,
NH.sub.2(cycloalkyl), HN(cycloalkyl).sub.2, N(cycloalkyl).sub.3),
mono-, di- or tri-arylamines (i.e., NH.sub.2(aryl), HN(aryl).sub.2,
N(aryl).sub.3), or mixed amines, etc. Specific examples of suitable
amines include, by way of example only, isopropylamine, trimethyl
amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,
ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,
morpholine, N-ethylpiperidine, and the like.
[0164] "Isomers" refers to compounds that have the same molecular
formula. As used herein, the term isomers include double bond
isomers, racemates, stereoisomers, enantiomers, diastereomers, and
atropisomers. Single isomers, such as enantiomers or diastereomers,
can be obtained by asymmetric synthesis or by resolution of a
mixture of isomers. Resolution of a mixture of isomers (e.g.
racemates) maybe accomplished, for example, by conventional methods
such as crystallization in the presence of a resolving agent, or
chromatography, using, for example a chiral high pressure liquid
chromatography (HPLC) column. "Double bond isomers" refer to Z- and
E-forms (or cis- and trans-forms) of the compounds with
carbon-carbon double bonds.
[0165] "Atropisomers" refers to conformational stereoisomers which
occur when rotation about a single bond in the molecule is
prevented, or greatly hindered, as a result of steric interactions
with other parts of the molecule and the substituents at both ends
of the single bond are asymmetrical, i.e., they do not require a
stereocenter. Where the rotational barrier about the single bond is
high enough, and interconversion between conformations is slow
enough, separation and isolation of the isomeric species may be
permitted. Atropisomers may be separated by the methods well known
in the art. Unless otherwise indicated, the description is intended
to include individual atropisomers as well as mixtures. Also, as
understood by those skilled in the art, the atropisomers may be
represented by the same chemical name with different atropisomer
designations. By way of example, the below structures are
atropisomers of compound 48.
##STR00189##
[0166] "Racemates" refers to a mixture of enantiomers.
[0167] "Stereoisomers" or "stereoisomeric forms" refer to compounds
that differ in the chirality of one or more stereocenters.
Stereoisomers include enantiomers and diastereomers. The compounds
may exist in stereoisomeric form if they possess one or more
asymmetric centers or a double bond with asymmetric substitution
and, therefore, can be produced as individual stereoisomers or as
mixtures. Unless otherwise indicated, the description is intended
to include individual stereoisomers as well as mixtures. The
methods for the determination of stereochemistry and the separation
of stereoisomers are well-known in the art (see, e.g., Chapter 4 of
Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons,
New York, 1992).
[0168] "Tautomers" or "tautomeric forms" refer to alternate forms
of a compound that differ in the position of a proton, such as
enol-keto and imine-enamine tautomers, or heteroaryls such as
pyrazoles, imidazoles, benzimidazoles, triazoles, and
tetrazoles.
[0169] A "solvate" is formed by the interaction of a solvent and a
compound. Solvates of salts of the compounds of any of the formulae
described herein are also provided. Hydrates of the compounds of
any of the formulae are also provided.
[0170] A "prodrug" is defined in the pharmaceutical field as a
biologically inactive derivative of a drug that upon administration
to the human body is converted to the biologically active parent
drug according to some chemical or enzymatic pathway. A prodrug is
thus a covalently modified analog or latent form of a
therapeutically active compound. Non-limiting examples of prodrugs
include ester moieties, quaternary ammonium moieties, glycol
moieties, and the like.
[0171] The application also provides a composition containing a
mixture of enantiomers of the compound or a pharmaceutically
acceptable salt thereof. In one embodiment, the mixture is a
racemic mixture. In other embodiments, the composition comprises
the (S)-enantiomer of a compound in excess of the corresponding
(R)-enantiomer of the compound. In some embodiments, the
composition contains the (S)-enantiomer of the compound and is
substantially free of its corresponding (R)-enantiomer. In certain
embodiments, a composition substantially free of the (R)-enantiomer
has less than or about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%,
0.05%, or 0.01% of the (R)-enantiomer. In other embodiments, the
composition containing the (S)-enantiomer of a compound or a
pharmaceutically acceptable salt thereof, predominates over its
corresponding (R)-enantiomer by a molar ratio of at least or about
9:1, at least or about 19:1, at least or about 40:1, at least or
about 80:1, at least or about 160:1, or at least or about
320:1.
[0172] The composition containing a compound according to any of
the formulae described herein or a pharmaceutically acceptable salt
thereof, may also contain the compound in enantiomeric excess
(e.e.). By way of example, a compound with 95% (S)-isomer and 5%
(R)-isomer will have an e.e. of 90%. In some embodiments, the
compound has an e.e. of at least or about 60%, 75%, 80%, 85%, 90%,
95%, 98% or 99%.
[0173] In any one of the foregoing embodiments, the compound or a
pharmaceutically acceptable salt thereof, is an atropisomer.
Another embodiment provides the composition containing a mixture of
atropisomers of the compound or a pharmaceutically acceptable salt
thereof. By way of example, a compound with 95% of one atropisomer
and 5% of the other atropisomers. In some embodiments, a compound
with about 90, 80, 70, 60, 50, 40, 30, 20, or 10% of one
atropisomer and 10, 20, 30, 40, 50, 60, 70, 80, or 90%,
respectively, of the other atropisomers.
[0174] The application also provides the free base forms of the
compounds described herein. In certain embodiments, provided herein
are the enantiomers, (R) or (S), of the compounds of the formulae
described herein. In other embodiments, provided herein are the
atropisomers of the compounds of the formulae described herein.
[0175] The application further provides compositions comprising the
compounds described herein or a pharmaceutically acceptable salt,
isomer, prodrug, or solvate thereof. The composition may include
racemic mixtures, mixtures containing an enantiomeric excess of one
enantiomer or single diastereomers or diastereomeric mixtures. All
such isomeric forms of these compounds are expressly included
herein, the same as if each and every isomeric form were
specifically and individually listed.
[0176] In certain embodiments, provided herein are also polymorphs,
such as crystalline and amorphous forms, of the compounds described
herein. In some embodiments, provided are also chelates,
non-covalent complexes, and mixtures thereof, of the compounds of
the formula described herein or pharmaceutically acceptable salts,
prodrugs, or solvates thereof. A "chelate" is formed by the
coordination of a compound to a metal ion at two (or more) points.
A "non-covalent complex" is formed by the interaction of a compound
and another molecule wherein a covalent bond is not formed between
the compound and the molecule. For example, complexation can occur
through van der Waals interactions, hydrogen bonding, and
electrostatic interactions (also called ionic bonding).
[0177] In certain embodiments, provided are also chelates,
non-covalent complexes, and mixtures thereof, of the compounds
described herein or a pharmaceutically acceptable salt, tautomer,
stereoisomer, mixture of stereoisomers, prodrug, or deuterated
analog thereof. A "chelate" is formed by the coordination of a
compound to a metal ion at two (or more) points. A "non-covalent
complex" is formed by the interaction of a compound and another
molecule wherein a covalent bond is not formed between the compound
and the molecule. For example, complexation can occur through van
der Waals interactions, hydrogen bonding, and electrostatic
interactions (also called ionic bonding).
[0178] Some of the compounds exist as tautomers. Tautomers are in
equilibrium with one another. For example, amide containing
compounds may exist in equilibrium with imidic acid tautomers.
Regardless of which tautomer is shown, and regardless of the nature
of the equilibrium among tautomers, the compounds are understood by
one of ordinary skill in the art to comprise both amide and imidic
acid tautomers. Thus, the amide containing compounds are understood
to include their imidic acid tautomers. Likewise, the imidic acid
containing compounds are understood to include their amide
tautomers.
[0179] Any formula or structure given herein, is also intended to
represent unlabeled forms as well as isotopically labeled forms of
the compounds. Isotopically labeled compounds have structures
depicted by the formulas given herein except that one or more atoms
are replaced by an atom having a selected atomic mass or mass
number. Examples of isotopes that can be incorporated into
compounds of the disclosure include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but
not limited to .sup.2H (deuterium, D), .sup.3H (tritium), .sup.11C,
.sup.13C, .sup.14C, .sup.15N, .sup.18F, .sup.31P, .sup.32P,
.sup.35S, .sup.36Cl and .sup.125I. Various isotopically labeled
compounds of the present disclosure, for example those into which
radioactive isotopes such as .sup.3H, .sup.13C and .sup.14C are
incorporated. Such isotopically labeled compounds may be useful in
metabolic studies, reaction kinetic studies, detection or imaging
techniques, such as positron emission tomography (PET) or
single-photon emission computed tomography (SPECT) including drug
or substrate tissue distribution assays or in radioactive treatment
of patients.
[0180] The disclosure also includes "deuterated analogs" of
compounds of Formula I in which from 1 to n hydrogens attached to a
carbon atom is/are replaced by deuterium, in which n is the number
of hydrogens in the molecule. Such compounds exhibit increased
resistance to metabolism and are thus useful for increasing the
half-life of any compound of Formula I when administered to a
mammal, particularly a human. See, for example, Foster, "Deuterium
Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.
Sci. 5(12):524-527 (1984). Such compounds are synthesized by means
well known in the art, for example by employing starting materials
in which one or more hydrogens have been replaced by deuterium.
[0181] Deuterium labeled or substituted therapeutic compounds of
the disclosure may have improved DMPK (drug metabolism and
pharmacokinetics) properties, relating to distribution, metabolism
and excretion (ADME). Substitution with heavier isotopes such as
deuterium may afford certain therapeutic advantages resulting from
greater metabolic stability, for example increased in vivo
half-life, reduced dosage requirements and/or an improvement in
therapeutic index. An .sup.18F labeled compound may be useful for
PET or SPECT studies. Isotopically labeled compounds of this
disclosure and prodrugs thereof can generally be prepared by
carrying out the procedures disclosed in the schemes or in the
examples and preparations described below by substituting a readily
available isotopically labeled reagent for a non-isotopically
labeled reagent. It is understood that deuterium in this context is
regarded as a substituent in the compound of Formula I.
[0182] The concentration of such a heavier isotope, specifically
deuterium, may be defined by an isotopic enrichment factor. In the
compounds of this disclosure any atom not specifically designated
as a particular isotope is meant to represent any stable isotope of
that atom. Unless otherwise stated, when a position is designated
specifically as "H" or "hydrogen", the position is understood to
have hydrogen at its natural abundance isotopic composition.
Accordingly, in the compounds of this disclosure any atom
specifically designated as a deuterium (D) is meant to represent
deuterium.
Therapeutic Uses of the Compounds
[0183] The compounds of the formulae described herein or a
pharmaceutically acceptable salt, isomer, prodrug, or solvate
thereof may be used for the treatment of diseases and/or conditions
mediated by PI3K isoforms. In addition, the application provides
the compounds for use in therapy. Also, provided herein are methods
for inhibiting one or more PI3K isoforms. In one embodiment,
provided are methods for inhibiting PI3K.beta. activity using the
compound described herein or a pharmaceutically acceptable salt,
isomer, prodrug, or solvate thereof. In other embodiment, provided
are methods for inhibiting PI3K.beta. activities using the compound
or a pharmaceutically acceptable salt, isomer, prodrug, or solvate
thereof. The application further provides methods for use in such
methods. The PI3K isoforms may be selectively or specifically
inhibited. Additionally, the compounds may be used to inhibit PI3K
activity therapeutically or prophylactically, such as
PI3K.beta..
[0184] The compounds according to the present application may be
used in combination with one or more additional therapeutic agents.
The therapeutic agents may be in the forms of compounds,
antibodies, polypeptides, or polynucleotides. The therapeutic agent
includes, but is not limited to, a chemotherapeutic agent, an
immunotherapeutic agent, a radiotherapeutic agent, an
anti-neoplastic agent, an anti-cancer agent, an anti-proliferation
agent, an anti-fibrotic agent, an anti-angiogenic agent, a
therapeutic antibody, or any combination thereof. In one
embodiment, the application provides a product comprising a
compound described herein and an additional therapeutic agent as a
combined preparation for simultaneous, separate or sequential use
in therapy, e.g. a method of treating a disease, disorder, or
condition that is mediated by PI3K isoforms. The compounds of the
invention can be used in combination with compounds that inhibit or
modulate the activities of poly(ADP-ribose) polymerases (PARP),
such as PARP-1, PARP-2, PARP-3 and Vault-PARP; Tankyrases (TANKs),
such as, TANK-1, TANK-2 and TANK-3; matrix metalloproteinases such
as MMP-2 and MMP-9; and androgen receptor.
[0185] Therapeutic agents that can be used in combination with
compounds of the invention include enzalutamide, abiraterone,
abiraterone acetate, apalutamide, galeterone, olaparib, niraparib,
veliparib, rucaparib, flutamide, nilutamide, bicalutamide,
ketonazole, orteronel, finasteride, dutasteride, bexlosteride,
izonsteride, turosteride, episteride, dexamethasone, prednisone,
leuprolide, goserelin, triptorelin, histrelin, estrogen,
cyproterone acetate, spironolactone, flutamide, hydroxyflutamide,
docetaxel, cabazitaxel, sipuleucel-T, ODM-201, VT-464, EPI-506, and
combinations thereof.
[0186] Also, the therapeutic agents may be those that inhibit or
modulate the activities of Bruton's tyrosine kinase, spleen
tyrosine kinase, apoptosis signal-regulating kinase, Janus kinase,
lysyl oxidase, lysyl oxidase-like proteins, matrix
metallopeptidase, bromodomain-containing protein, adenosine A2B
receptor, isocitrate dehydrogenase, serine/threonine kinase TPL2,
discoidin domain receptor, serine/threonine-protein kinases, IKK,
MEK, EGFR, histone deacetylase, protein kinase C, or any
combination thereof. In certain embodiments, the therapeutic agent
may be selected from a PI3K (including PI3K.gamma., PI3K.delta.,
PI3K.beta., PI3K.alpha., and/or pan-PI3K) inhibitor, a JAK (Janus
kinase, including JAK1, JAK2, and/or JAK3) inhibitor, a SYK (spleen
tyrosine kinase) inhibitor, a BTK (Bruton's tyrosine kinase)
inhibitor, an A2B (adenosine A2B receptor) inhibitor, an ACK
(activated CDC kinase, including ACK1) inhibitor, an ASK (apoptosis
signal-regulating kinase, including ASK1) inhibitor, Aurora kinase,
a BRD (bromodomain-containing protein, including BRD4) inhibitor, a
Bcl (B-cell CLL/lymphoma, including Bcl-1 and/or Bcl-2) inhibitor,
a CAK (CDK-activating kinase) inhibitor, a CaMK
(calmodulin-dependent protein kinases) inhibitor, a CDK
(cyclin-dependent kinases, including CDK1, 2, 3, 4, and/or 6)
inhibitor, a CK (casein kinase, including CK1 and/or CK2)
inhibitor, a DDR (discoidin domain receptor, including DDR1 and/or
DDR2) inhibitor, a EGFR inhibitor, a FXR (farnesoid x receptor)
inhibitor, a FAK (focal adhesion kinase) inhibitor, a GSK (glycogen
synthase kinase) inhibitor, a HDAC (histone deacetylase) inhibitor,
an IDO (indoleamine 2,3-dioxygenase) inhibitor, an IDH (isocitrate
dehydrogenase, including IDH1) inhibitor, an IKK (1-Kappa-B kinase)
inhibitor, a KDMS (lysine demethylase) inhibitor, a LCK
(lymphocyte-specific protein tyrosine kinase) inhibitor, a LOX
(lysyl oxidase) inhibitor, a LOXL (lysyl oxidase like protein,
including LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL5) inhibitor, a
MTH (mut T homolog) inhibitor, a MEK (mitogen-activated protein
kinase kinase) inhibitor, a matrix metalloprotease (MMP, including
MMP2 and/or MMP9) inhibitor, a mitogen-activated protein kinases
(MAPK) inhibitor, a PD-1 (programmed cell death protein 1)
inhibitor, a PD-L1 (programmed death-ligand 1) inhibitor, a PDGF
(platelet-derived growth factor) inhibitor, a phosphorylase kinase
(PK) inhibitor, a PLK (polo-like kinase, including PLK1, 2, 3)
inhibitor, a protein kinase (PK, including protein kinase A, B, C)
inhibitor, a STK (serine/threonine kinase) inhibitor, a STAT
(signal transduction and transcription) inhibitor, a
serine/threonine-protein kinase inhibitor, a TBK (tank-binding
kinase) inhibitor, a TLR (toll-like receptor modulators, including
TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9,
TLR-10, TLR-11, TLR-12, and/or TLR-13) inhibitor, a TK (tyrosine
kinase) inhibitor, a TPL2 (serine/threonine kinase) inhibitor, a
NEK9 inhibitor, an Abl inhibitor, a p38 kinase inhibitor, a PYK
inhibitor, a PYK inhibitor, a c-Kit inhibitor, a NPM-ALK inhibitor,
a Flt-3 inhibitor, a c-Met inhibitor, a KDR inhibitor, a TIE-2
inhibitor, a VEGFR inhibitor, a SRC inhibitor, a HCK inhibitor, a
LYN inhibitor, a FYN inhibitor, a YES inhibitor, a chemotherapeutic
agent, an immunotherapeutic agent, a radiotherapeutic agent, an
anti-neoplastic agent, an anti-cancer agent, an anti-proliferation
agent, an anti-fibrotic agent, an anti-angiogenic agent, a
therapeutic antibody, or any combination thereof. In some
embodiments, the JAK inhibitor is
N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide
as named by ChemDraw (may also be referred to as CYT0387 or
momelotinib) and may be synthesized by the methods described in
U.S. Pat. No. 8,486,941. In certain embodiment, the SyK inhibitor
is
6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine
as named by ChemDraw (may also be referred to as
6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-a-
mine) and may be synthesized by the methods described in U.S. Pat.
No. 8,450,321. In other embodiments, the BTK inhibitor is
(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-pur-
in-8(9H)-one as named by ChemDraw (may also be
6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-di-
hydro-8H-purin-8-one) and may be synthesized by the methods in U.S.
Pat. No. 8,557,803.
[0187] Chemotherapeutic agents may be categorized by their
mechanism of action into, for example, the following groups:
anti-metabolites/anti-cancer agents, such as pyrimidine analogs
(floxuridine, capecitabine, and cytarabine); purine analogs, folate
antagonists and related inhibitors, antiproliferative/antimitotic
agents including natural products such as vinca alkaloid
(vinblastine, vincristine) and microtubule such as taxane
(paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and
navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA
damaging agents (actinomycin, amsacrine, busulfan, carboplatin,
chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin,
daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan,
merchlorehtamine, mitomycin, mitoxantrone, nitrosourea,
procarbazine, taxol, taxotere, teniposide, etoposide,
triethylenethiophosphoramide); antibiotics such as dactinomycin
(actinomycin D), daunorubicin, doxorubicin (adriamycin),
idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin
(mithramycin) and mitomycin; enzymes (L-asparaginase which
systemically metabolizes L-asparagine and deprives cells which do
not have the capacity to synthesize their own asparagine);
antiplatelet agents; antiproliferative/antimitotic alkylating
agents such as nitrogen mustards cyclophosphamide and analogs,
melphalan, chlorambucil), and (hexamethylmelamine and thiotepa),
alkyl nitrosoureas (BCNU) and analogs, streptozocin),
trazenes-dacarbazinine (DTIC); antiproliferative/antimitotic
antimetabolites such as folic acid analogs (methotrexate); platinum
coordination complexes (cisplatin, oxiloplatinim, carboplatin),
procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones,
hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide,
nilutamide) and aromatase inhibitors (letrozole, anastrozole);
anticoagulants (heparin, synthetic heparin salts and other
inhibitors of thrombin); fibrinolytic agents (such as tissue
plasminogen activator, streptokinase and urokinase), aspirin,
dipyridamole, ticlopidine, clopidogrel; antimigratory agents;
antisecretory agents (breveldin); immunosuppressives (tacrolimus,
sirolimus azathioprine, mycophenolate); phytoestrogens (daidzein,
glycitein, genisteinand growth factor inhibitors (vascular
endothelial growth factor inhibitors, fibroblast growth factor
inhibitors); angiotensin receptor blocker, nitric oxide donors;
anti-sense oligonucleotides; antibodies (trastuzumab, rituximab);
cell cycle inhibitors and differentiation inducers (tretinoin);
inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin),
daunorubicin, dactinomycin, eniposide, epirubicin, etoposide,
idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan,
camptothesin), corticosteroids (cortisone, dexamethasone,
hydrocortisone, methylprednisolone, prednisone, and prednisolone);
growth factor signal transduction kinase inhibitors; dysfunction
inducers, toxins such as Cholera toxin, ricin, Pseudomonas
exotoxin, Bordetella pertussis adenylate cyclase toxin, or
diphtheria toxin, and caspase activators; and chromatin.
[0188] As used herein the term "chemotherapeutic agent" or
"chemotherapeutic" (or "chemotherapy," in the case of treatment
with a chemotherapeutic agent) is meant to encompass any
non-proteinaceous (i.e., non-peptidic) chemical compound useful in
the treatment of cancer. Examples of chemotherapeutic agents
include alkylating agents such as thiotepa and cyclophosphamide
(CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and
piposulfan; aziridines such as benzodopa, carboquone, meturedopa,
and uredopa; emylerumines and memylamelamines including
alfretamine, triemylenemelamine, triethylenephosphoramide,
triethylenethiophosphoramide and trimemylolomelamine; acetogenins
(especially bullatacin and bullatacinone); a camptothecin
(including synthetic analogue topotecan); bryostatin; callystatin;
CC-1065 (including its adozelesin, carzelesin and bizelesin
synthetic analogues); cryptophycins (articularly cryptophycin 1 and
cryptophycin 8); dolastatin; duocarmycin (including the synthetic
analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a
sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,
chlornaphazine, cholophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosoureas such as carmustine, chlorozotocin,
foremustine, lomustine, nimustine, ranimustine; antibiotics such as
the enediyne antibiotics (e.g., calicheamicin, especially
calicheamicin gammaII and calicheamicin phiI1, see, e.g., Agnew,
Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including
dynemicin A; bisphosphonates, such as clodronate; an esperamicin;
as well as neocarzinostatin chromophore and related chromoprotein
enediyne antibiotic chromomophores), aclacinomysins, actinomycin,
authramycin, azaserine, bleomycins, cactinomycin, carabicin,
carrninomycin, carzinophilin, chromomycins, dactinomycin,
daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin
(including morpholino-doxorubicin, cyanomorpholino-doxorubicin,
2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin
C, mycophenolic acid, nogalamycin, olivomycins, peplomycin,
potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;
anti-metabolites such as methotrexate and 5-fluorouracil (5-FU);
folic acid analogues such as demopterin, methotrexate, pteropterin,
trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine,
thiamiprine, thioguanine; pyrimidine analogues such as ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine, floxuridine; androgens such as
calusterone, dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replinisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate;
defofamine; demecolcine; diaziquone; elformthine; elliptinium
acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;
lentinan; leucovorin; lonidamine; maytansinoids such as maytansine
and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine;
pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine;
folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine;
PSK.RTM.; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic
acid; triaziquone; 2,2',2''-tricUorotriemylamine; trichothecenes
(especially T-2 toxin, verracurin A, roridin A and anguidine);
urethane; vindesine; dacarbazine; mannomustine; mitobronitol;
mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL.RTM.
and docetaxel (TAXOTERE.RTM.); chlorambucil; gemcitabine
(Gemzar.RTM.); 6-thioguanine; mercaptopurine; methotrexate;
platinum analogs such as cisplatin and carboplatin; vinblastine;
platinum; etoposide (VP-16); ifosfamide; mitroxantrone;
vancristine; vinorelbine (Navelbine.RTM.); novantrone; teniposide;
edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11;
topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);
retinoids such as retinoic acid; capecitabine; FOLFIRI
(fluorouracil, leucovorin, and irinotecan) and pharmaceutically
acceptable salts, acids or derivatives of any of the above. One or
more chemotherapeutic agent are used or included in the present
application.
[0189] Also included in the definition of "chemotherapeutic agent"
are anti-hormonal agents that act to regulate or inhibit hormone
action on tumors such as anti-estrogens and selective estrogen
receptor modulators (SERMs), including, for example, tamoxifen
(including Nolvadex.TM.), raloxifene, droloxifene,
4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone,
and toremifene (Fareston.RTM.); inhibitors of the enzyme aromatase,
which regulates estrogen production in the adrenal glands, such as,
for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate
(Megace.RTM.), exemestane, formestane, fadrozole, vorozole
(Rivisor.RTM.), letrozole (Femara.RTM.), and anastrozole
(Arimidex.RTM..); and anti-androgens such as flutamide, nilutamide,
bicalutamide, leuprohde, and goserelin; and pharmaceutically
acceptable salts, acids or derivatives of any of the above.
[0190] The anti-angiogenic agents include, but are not limited to,
retinoid acid and derivatives thereof, 2-methoxyestradiol,
ANGIOSTATIN.RTM., ENDOSTATIN.RTM., suramin, squalamine, tissue
inhibitor of metalloproteinase-1, tissue inhibitor of
metalloproternase-2, plasminogen activator inhibitor-1, plasminogen
activator inhibitor-2, cartilage-derived inhibitor, paclitaxel
(nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine),
sulphated chitin derivatives (prepared from queen crab shells),
sulphated polysaccharide peptidoglycan complex (sp-pg),
staurosporine, modulators of matrix metabolism, including for
example, proline analogs ((1-azetidine-2-carboxylic acid (LACA),
cishydroxyproline, d,I-3,4-dehydroproline, thiaproline,
.alpha.-dipyridyl, beta-aminopropionitrile fumarate,
4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate,
mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3,
chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin;
fumagillin, gold sodium thiomalate, d-penicillamine (CDPT),
beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene,
lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid
disodium or "CCA", thalidomide; angiostatic steroid,
carboxynaminoimidazole; metalloproteinase inhibitors such as BB94.
Other anti-angiogenesis agents include antibodies, preferably
monoclonal antibodies against these angiogenic growth factors:
beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and
Ang-1/Ang-2. See Ferrara N. and Alitalo, K. "Clinical application
of angiogenic growth factors and their inhibitors" (1999) Nature
Medicine 5:1359-1364.
[0191] The anti-fibrotic agents include, but are not limited to,
the compounds such as beta-aminoproprionitrile (BAPN), as well as
the compounds disclosed in U.S. Pat. No. 4,965,288 to Palfreyman,
et al., issued Oct. 23, 1990, entitled "Inhibitors of lysyl
oxidase," relating to inhibitors of lysyl oxidase and their use in
the treatment of diseases and conditions associated with the
abnormal deposition of collagen; U.S. Pat. No. 4,997,854 to Kagan,
et al., issued Mar. 5, 1991, entitled "Anti-fibrotic agents and
methods for inhibiting the activity of lysyl oxidase in situ using
adjacently positioned diamine analogue substrate," relating to
compounds which inhibit LOX for the treatment of various
pathological fibrotic states, which are herein incorporated by
reference. Further exemplary inhibitors are described in U.S. Pat.
No. 4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled
"Inhibitors of lysyl oxidase," relating to compounds such as
2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as,
e.g., U.S. Pat. No. 5,021,456; U.S. Pat. No. 5,5059,714; U.S. Pat.
No. 5,120,764; U.S. Pat. No. 5,182,297; U.S. Pat. No. 5,252,608
(relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S.
Patent Application No. 2004/0248871, which are herein incorporated
by reference. Exemplary anti-fibrotic agents also include the
primary amines reacting with the carbonyl group of the active site
of the lysyl oxidases, and more particularly those which produce,
after binding with the carbonyl, a product stabilized by resonance,
such as the following primary amines: emylenemamine, hydrazine,
phenylhydrazine, and their derivatives, semicarbazide, and urea
derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN),
or 2-nitroethylamine, unsaturated or saturated haloamines, such as
2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine,
3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone.
Also, the anti-fibrotic agents are copper chelating agents,
penetrating or not penetrating the cells. Exemplary compounds
include indirect inhibitors such compounds blocking the aldehyde
derivatives originating from the oxidative deamination of the lysyl
and hydroxylysyl residues by the lysyl oxidases, such as the
thiolamines, in particular D-penicillamine, or its analogues such
as 2-amino-5-mercapto-5-methylhexanoic acid,
D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,
p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,
sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane
sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate,
sodium-4-mercaptobutanesulphinate trihydrate.
[0192] The immunotherapeutic agents include and are not limited to
therapeutic antibodies suitable for treating patients; such as
abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab,
amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab,
bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab,
catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab,
conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab,
detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab,
ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab,
figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab,
girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab,
indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab,
labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab,
mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab,
moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab,
nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab,
oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab,
pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab,
radretumab, rilotumumab, rituximab, robatumumab, satumomab,
sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab,
taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab,
trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab,
votumumab, zalutumumab, obinutuzumab, CC49 and 3F8. The exemplified
therapeutic antibodies may be further labeled or combined with a
radioisotope particle, such as indium In 111, yttrium Y 90, iodine
I-131.
[0193] The application also provides method for treating a subject
who is undergoing one or more standard therapies, such as
chemotherapy, radiotherapy, immunotherapy, surgery, or combination
thereof. Accordingly, one or more therapeutic agent or inhibitors
may be administered before, during, or after administration of
chemotherapy, radiotherapy, immunotherapy, surgery or combination
thereof.
[0194] Other examples of chemotherapy treatments (including
standard or experimental chemotherapies) are described below. In
addition, treatment of certain lymphomas is reviewed in Cheson, B.
D., Leonard, J. P., "Monoclonal Antibody Therapy for B-Cell
Non-Hodgkin's Lymphoma" The New England Journal of Medicine 2008,
359(6), p. 613-626; and Wierda, W. G., "Current and Investigational
Therapies for Patients with CLL" Hematology 2006, p. 285-294.
Lymphoma incidence patterns in the United States is profiled in
Morton, L. M., et al. "Lymphoma Incidence Patterns by WHO Subtype
in the United States, 1992-2001" Blood 2006, 107(1), p.
265-276.
[0195] Examples of immunotherapeutic agents include, but are not
limited to, rituximab (such as Rituxan), alemtuzumab (such as
Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies,
anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5
antibodies, anti-CD74 antibodies, apolizumab, bevacizumab,
CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody),
galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab,
ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1
126-134 peptide vaccine, tositumomab, autologous human
tumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy
agents includes using cancer vaccines based upon the genetic makeup
of an individual patient's tumor, such as lymphoma vaccine example
is GTOP-99 (MyVax.RTM.).
[0196] Examples of chemotherapy agents include aldesleukin,
alvocidib, antineoplaston AS2-1, antineoplaston A10, anti-thymocyte
globulin, amifostine trihydrate, aminocamptothecin, arsenic
trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263,
ABT-199, BMS-345541, bortezomib (Velcade.RTM.), bryostatin 1,
busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin
acetate, clofarabine, cisplatin, Cladribine (Leustarin),
Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclophosphamide
(Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, denileukin
diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10,
Doxorubicin (Adriamycin.RTM., Adriblastine), doxorubicin
hydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus
(RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol,
Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide,
irinotecan hydrochloride, ixabepilone, Lenalidomide (Revlimid.RTM.,
CC-5013), lymphokine-activated killer cells, melphalan,
methotrexate, mitoxantrone hydrochloride, motexafin gadolinium,
mycophenolate mofetil, nelarabine, oblimersen (Genasense) Obatoclax
(GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids,
oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin
hydrochloride, pegfilgrastim, Pentstatin (Nipent), perifosine,
Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202),
recombinant interferon alfa, recombinant interleukin-12,
recombinant interleukin-11, recombinant flt3 ligand, recombinant
human thrombopoietin, rituximab, sargramostim, sildenafil citrate,
simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin,
Temsirolimus (CC1-779), Thalidomide, therapeutic allogeneic
lymphocytes, thiotepa, tipifarnib, Velcade.RTM. (bortezomib or
PS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbine
ditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine,
rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone), CVP (cyclophosphamide, vincristine and prednisone),
FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR
(fludarabine, cyclophosphamide, rituximab), hyperCVAD
(hyperfractionated cyclophosphamide, vincristine, doxorubicin,
dexamethasone, methotrexate, cytarabine), ICE (iphosphamide,
carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and
prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus
CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP
(R-MCP).
[0197] The therapeutic treatments can be supplemented or combined
with any of the abovementioned therapies with stem cell
transplantation or treatment. One example of modified approach is
radioimmunotherapy, wherein a monoclonal antibody is combined with
a radioisotope particle, such as indium In 111, yttrium Y 90,
iodine I-131. Examples of combination therapies include, but are
not limited to, Iodine-131 tositumomab (Bexxar.RTM.), Yttrium-90
ibritumomab tiuxetan (Zevalin.RTM.), Bexxar.RTM. with CHOP.
[0198] Other therapeutic procedures include peripheral blood stem
cell transplantation, autologous hematopoietic stem cell
transplantation, autologous bone marrow transplantation, antibody
therapy, biological therapy, enzyme inhibitor therapy, total body
irradiation, infusion of stem cells, bone marrow ablation with stem
cell support, in vitro-treated peripheral blood stem cell
transplantation, umbilical cord blood transplantation, immunoenzyme
technique, pharmacological study, low-LET cobalt-60 gamma ray
therapy, bleomycin, conventional surgery, radiation therapy, and
nonmyeloablative allogeneic hematopoietic stem cell
transplantation.
[0199] In some embodiments, the methods include administering a
compound of the formula described herein or a pharmaceutically
acceptable salt, isomer, prodrug, or solvate thereof, in a
therapeutically effective amount to a human in need thereof. The
method can be employed to treat a patient who has or is believed to
have a disease or condition whose symptoms or pathology is mediated
by expression or activity of PI3K.beta.. The patient may be a
mammal or a human. In certain embodiment, the patient may be a
human.
[0200] "Treatment" or "treating" is an approach for obtaining
beneficial or desired results including clinical results.
Beneficial or desired clinical results may include one or more of
the following: a) inhibiting the disease or condition (e.g.,
decreasing one or more symptoms resulting from the disease or
condition, and/or diminishing the extent of the disease or
condition); b) slowing or arresting the development of one or more
clinical symptoms associated with the disease or condition (e.g.,
stabilizing the disease or condition, preventing or delaying the
worsening or progression of the disease or condition, and/or
preventing or delaying the spread (e.g., metastasis) of the disease
or condition); and/or c) relieving the disease, that is, causing
the regression of clinical symptoms (e.g., ameliorating the disease
state, providing partial or total remission of the disease or
condition, enhancing the effect of another medication, delaying the
progression of the disease, increasing the quality of life, and/or
prolonging survival.
[0201] "Prevention" or "preventing" means any treatment of a
disease or condition that causes the clinical symptoms of the
disease or condition not to develop. Compounds may, in some
embodiments, be administered to a subject (including a human) who
is at risk or has a family history of the disease or condition.
[0202] "Subject" or "patient" refer to an animal, such as a mammal
(including a human), that has been or will be the object of
treatment, observation or experiment. The methods described herein
may be useful in human therapy and/or veterinary applications. In
some embodiments, the subject is a mammal. In one embodiment, the
subject is a human "Human in need thereof" refers to a human who
may have or is suspect to have diseases, or disorders, or
conditions that would benefit from certain treatment; for example,
being treated with the PI3K inhibitor of the compounds according to
the present application. In certain embodiments, the subject may be
a human who (i) has not received any treatment including
chemotherapy treatment, (ii) is substantially refractory to at
least one chemotherapy treatment, (iii) is in relapse after
treatment with chemotherapy, or both (i) and (ii). In some of
embodiments, the subject is refractory to at least one, at least
two, at least three, or at least four chemotherapy treatments
(including standard or experimental chemotherapies).
[0203] The terms "therapeutically effective amount" or "effective
amount" of a compound of the present application or a
pharmaceutically acceptable salt, isomers, prodrug, or solvate
thereof, mean an amount sufficient to effect treatment when
administered to a subject, to provide a therapeutic benefit such as
amelioration of symptoms or slowing of disease progression. For
example, a therapeutically effective amount may be an amount
sufficient to decrease a symptom of a disease or condition
responsive to inhibition of PI3K.delta. and PI3K.beta. activity.
The therapeutically effective amount may vary depending on the
subject, and disease or condition being treated, the weight and age
of the subject, the severity of the disease or condition, and the
manner of administering, which can readily be determined by one or
ordinary skill in the art.
[0204] In addition to the therapeutic uses, the compounds described
herein have the selectivity or selective inhibition to certain PI3K
isoforms. In one embodiment, the compounds have selectivity to
PI3K.beta.. The selectivity to PI3K isoforms may be determined by
measuring the compound's activity in inhibiting certain PI3K
isoforms using the assay described in the example below or the
methods commonly used. It is understood that the conditions (e.g.
the reagent concentration or the incubation temperature) may be
varied and the results of the assay may vary. In some instances,
the value may vary within a range of one to three-fold.
[0205] The term "inhibition" indicates a decrease in the baseline
activity of a biological activity or process. The term "inhibition
of activity of PI3K isoforms" or variants thereof refer to a
decrease in activity in any PI3K isoform (e.g., alpha, beta, gamma,
or delta) as a direct or indirect response to the presence of a
compound of any of the formula described herein relative to the
activity of PI3K isoform in the absence of such compound.
"Inhibition of PI3K.delta. and/or PI3K.beta. activities" or
variants thereof refer to a decrease in PI3K.delta. and/or
PI3K.beta. activities as a direct or indirect response to the
presence of the compounds described herein, relative to the
activities of PI3K.delta. and/or PI3K.beta. in the absence of such
compound. In some embodiments, the inhibition of PI3K isoform
activities may be compared in the same subject prior to treatment,
or other subjects not receiving the treatment.
[0206] Without being bound to any theory, the decrease in the
activity of PI3K may be due to the direct interaction of the
compound with PI3K, or due to the interaction of the compounds
described herein with one or more other factors that affect PI3K
activity. For example, the presence of the compounds may decrease
the activities of PI3K.delta. and/or PI3K.beta. by directly binding
to PI3K.delta. and/or PI3K.beta., by causing (directly or
indirectly) another factor to decrease PI3K.delta. and/or
PI3K.beta. activities, or by (directly or indirectly) decreasing
the amount of PI3K.delta. and/or PI3K.beta. present in the cell or
organism.
[0207] The term "PI3K inhibitor" or variant thereof refers to a
compound that inhibits the activity of PI3K. The term "PI3K isoform
selective inhibitor" or variant thereof refers to a compound that
inhibits the activity of one or more PI3K isoforms more effectively
than the other remaining PI3K isoforms. By way of example, the term
"PI3K.beta. selective inhibitor" generally refers to a compound
that inhibits the activity of the PI3K.beta. isoform more
effectively than other isoforms of the PI3K family, and the term
"PI3K.delta. selective inhibitor" generally refers to a compound
that inhibits the activity of the PI3K.delta. isoform more
effectively than other isoforms of the PI3K family. The term "dual
PI3K.delta./.beta. selective inhibitor" generally refers to a
compound that inhibits the activity of both PI3K.delta. and
PI3K.beta. isoforms more effectively than other isoforms of the
PI3K family (e.g., PI3K .alpha. or .gamma.).
[0208] The relative efficacies of compounds as inhibitors of an
enzyme activity (or other biological activity) can be established
by determining the concentrations at which each compound inhibits
the activity to a predefined extent and then comparing the results.
In one embodiment, the efficacy of a compound as an inhibitor of
one or more PI3K isoforms can be measured by the compound
concentration that inhibits 50% of the activity in a biochemical
assay, i.e., the 50% inhibitory concentration or "IC.sub.50". The
determination of IC.sub.50 values can be accomplished using
conventional techniques known in the art, including the techniques
described in the Examples below. In general, an IC.sub.50 can be
determined by measuring the activity of a given enzyme in the
presence of a range of concentrations of the compound under the
study. The experimentally obtained values of enzyme activity may
then be plotted against the compound concentrations used. The
concentration of the inhibitor that shows 50% enzyme activity (as
compared to the activity in the absence of any inhibitor) is taken
as the IC.sub.50 value. Analogously, other inhibitory
concentrations can be defined through appropriate determinations of
activity. For example, in some settings it may be desirable to
establish a 90% inhibitory concentration, i.e., IC.sub.90.
[0209] According to the present application, a PI3K.beta. selective
inhibitor is a compound that exhibits a 50% inhibitory
concentration (IC.sub.50) with respect to PI3K.beta. that is at
least 10-fold, at least 20-fold, at least 30-fold, at least
50-fold, at least 100-fold, at least 200-fold, or at least 500-fold
lower than the IC.sub.50 with respect to either PI3K.alpha. or
PI3K.gamma. or both PI3K.alpha. and PI3K.gamma.. In addition, a
PI3K.delta./.beta. selective inhibitor is a compound that exhibits
a 50% inhibitory concentration (IC.sub.50) with respect to
PI3K.beta. and PI3K.delta. that is at least 10-fold, at least
20-fold, at least 30-fold, at least 50-fold, at least 75-fold, at
least 100-fold, at least 200-fold, and at least 500-fold lower than
the IC.sub.50 with respect to either PI3K.alpha. or PI3K.gamma..
The dual PI3K.delta./.beta. selective inhibitor may have the same
or similar IC.sub.50 to both PI3K.delta. and PI3K.beta. or may have
different IC.sub.50 to either PI3K.delta. or PI3K.beta.. As used
herein, the term "potency," "potent," or variants thereof refer to
the compound exhibiting an IC.sub.50 value that is less than 100
nM. When comparing two compounds, the compound that exhibits a
lower IC.sub.50 value is referred to as a more potent
inhibitor.
[0210] The methods described herein may be applied to cell
populations in vivo or ex vivo. "In vivo" means within a living
individual, as within an animal or human. In this context, the
methods described herein may be used therapeutically in an
individual. "Ex vivo" means outside of a living individual.
Examples of ex vivo cell populations include in vitro cell cultures
and biological samples including fluid or tissue samples obtained
from individuals. Such samples may be obtained by methods well
known in the art. Exemplary biological fluid samples include blood,
cerebrospinal fluid, urine, and saliva. Exemplary tissue samples
include tumors and biopsies thereof. In this context, the compounds
may be used for a variety of purposes, including therapeutic and
experimental purposes. For example, it may be used ex vivo to
determine the optimal schedule and/or dosing of administration of a
PI3K selective inhibitor for a given indication, cell type,
individual, and other parameters. Information gleaned from such use
may be used for experimental purposes or in the clinic to set
protocols for in vivo treatment. Other ex vivo uses for which the
compound described herein may be suited are described below or will
become apparent to those skilled in the art. The compounds of the
formula described herein or a pharmaceutically acceptable salt,
prodrug, or solvate thereof, may be further characterized to
examine the safety or tolerance dosage in human or non-human
subjects. Such properties may be examined using commonly known
methods to those skilled in the art.
[0211] Compared to other PI3K isoforms, PI3K.beta. is generally
mis-regulated in certain cancer cells. Aberrant proliferation of
cells often interferes with normal tissue function, which may
result in abnormal cellular response such as immunity,
inflammation, and/or apoptosis. The selective inhibitors to
PI3K.beta. are useful in treating, inhibiting, or preventing
aberrant proliferation of cancerous and/or hematopoietic cells and
ameliorating the symptoms and secondary conditions.
[0212] The compounds described herein may be used to treat subjects
having various disease states, disorders, and conditions (also
collectively referred to as "indications") associated with PI3K
isoforms or their activities. As used herein, the terms "diseases,"
"disorders," "conditions" are used interchangeably. Such
indications may include, for example, cancer, including hematologic
malignancies (e.g. leukemias and lymphomas, myeloproliferative
disorders, myelodysplastic syndromes, plasma cell neoplasms) and
solid tumors, inflammation, fibrosis, allergic conditions
(including hypersensitivity), cardiovascular diseases,
neurodegenerative diseases, renal disorders, viral infections,
obesity, and autoimmune diseases.
[0213] In other embodiments, the compounds described herein may be
used to treat cancers that are mediated by, dependent on, or
associated with PI3K activity. In certain embodiments, the disease
or condition is an autoimmune disease, an inflammatory disease, or
a cancer. In some embodiments, the disease or condition is chosen
from rheumatoid arthritis, osteoarthritis, atherosclerosis,
psoriasis, systemic lupus erythematosus, multiple sclerosis,
inflammatory bowel disease, asthma, chronic obstructive airways
disease, pneumonitis, dermatitis, alopecia, nephritis, vasculitis,
atherosclerosis, Alzheimer's disease, hepatitis, primary biliary
cirrhosis, sclerosing cholangitis, diabetes (including type I
diabetes), acute rejection of transplanted organs, lymphomas,
multiple myelomas, leukemias, neoplasms and solid tumors.
[0214] In other embodiments, the disease is a solid tumor. By way
of examples, the solid tumor includes but is not limited to
prostate cancer, (including castration-resistant prostate cancer),
pancreatic cancer, bladder cancer, colorectal cancer, breast
cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian
cancer, cervical cancer, rectum cancer, liver cancer, kidney
cancer, stomach cancer, skin cancer, gastric cancer, esophageal
cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS
cancers (e.g., neuroblastoma), brain tumors (e.g., glioma,
anaplastic oligodendroglioma, adult glioblastoma multiforme, and
adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma.
In some embodiments, the solid tumor is non-small cell lung cancer,
small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian
cancer, renal cancer, pancreatic cancer, prostate cancer, or breast
cancer.
[0215] The present application also provides a method for treating
a human in need thereof, who has or is suspected of having a
disease or condition responsive or believed to be responsive to the
inhibition PI3K.beta. activity by administering to the subject a
compound of the formulae described herein or a pharmaceutically
acceptable salt, enantiomer, atropisomer, tautomer, prodrug, or
solvate thereof.
[0216] Additionally, the application provides a method of
inhibiting kinase activity of a PI3K.beta. polypeptides by
contacting the polypeptides with a compound of the formulae
described herein or a pharmaceutically acceptable salt, isomer,
prodrug, solvate, or a mixture thereof.
[0217] Moreover, the application provides a method of decreasing
cell viability, increasing cell death or apoptosis, increasing
interference with PI3K signaling pathways (including AKT, S6RP, ERK
phosphorylation), and/or reduction in chemokine production with an
effective amount of a compound of any of the formulae described
herein or a pharmaceutically acceptable salt, isomer, prodrug,
solvate, or a mixture thereof.
[0218] The application further provides a method of disrupting
leukocyte function comprising contacting the leukocytes with an
effective amount of a compound of any of the formulae described
herein or a pharmaceutically acceptable salt, isomer, prodrug,
solvate, or a mixture thereof, in a human in need thereof.
[0219] Provided is also a method of inhibiting growth or
proliferation of cancer cells comprising contacting the cancer
cells with an effective amount of a compound of the formulae
described herein or a pharmaceutically acceptable salt, isomer,
prodrug, solvate, or a mixture thereof.
Kits
[0220] Provided herein are also kits that include a compound of the
formulae of the present application or a pharmaceutically
acceptable salt, isomer, prodrug, or solvate thereof, and suitable
packaging. In one embodiment, a kit further includes instructions
for use. In one aspect, a kit includes a compound of the formulae
described herein or a pharmaceutically acceptable salt, isomer,
prodrug, or solvate thereof, and a label and/or instructions for
use of the compounds in the treatment of the indications, including
the diseases or conditions, described herein.
[0221] Provided herein are also articles of manufacture that
include a compound of any of the formulae described herein or a
pharmaceutically acceptable salt, isomer, prodrug, or solvate
thereof, in a suitable container. The container may be a vial, jar,
ampoule, preloaded syringe, and intravenous bag.
Pharmaceutical Compositions and Modes of Administration
[0222] Compounds provided herein are usually administered in the
form of pharmaceutical compositions. Thus, provides herein are also
pharmaceutical compositions that contain one or more of the
compounds of any of the formulae disclosed herein or a
pharmaceutically acceptable salt, isomers, prodrug, or solvate
thereof, and one or more pharmaceutically acceptable vehicles
selected from carriers, adjuvants and excipients. Suitable
pharmaceutically acceptable vehicles may include, for example,
inert solid diluents and fillers, diluents, including sterile
aqueous solution and various organic solvents, permeation
enhancers, solubilizers and adjuvants. Such compositions are
prepared in a manner well known in the pharmaceutical art. See,
e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co.,
Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel
Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).
[0223] The pharmaceutical compositions may be administered in
either single or multiple doses. The pharmaceutical composition may
be administered by various methods including, for example, rectal,
buccal, intranasal and transdermal routes. In certain embodiments,
the pharmaceutical composition may be administered by
intra-arterial injection, intravenously, intraperitoneally,
parenterally, intramuscularly, subcutaneously, orally, topically,
or as an inhalant. In some embodiments, the pharmaceutical
composition is administered orally.
[0224] One mode for administration is parenteral, for example, by
injection. The forms in which the pharmaceutical compositions
described herein may be incorporated for administration by
injection include, for example, aqueous or oil suspensions, or
emulsions, with sesame oil, corn oil, cottonseed oil, or peanut
oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous
solution, and similar pharmaceutical vehicles.
[0225] Oral administration may be another route for administration
of the compounds described herein. Administration may be via, for
example, capsule or enteric coated tablets. In making the
pharmaceutical compositions that include at least one compound of
any of the formulae described herein or a pharmaceutically
acceptable salt, prodrug, or solvate thereof, the active ingredient
is usually diluted by an excipient and/or enclosed within such a
carrier that can be in the form of a capsule, sachet, paper or
other container. When the excipient serves as a diluent, it can be
in the form of a solid, semi-solid, or liquid material, which acts
as a vehicle, carrier or medium for the active ingredient. Thus,
the compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions,
solutions, syrups, aerosols (as a solid or in a liquid medium),
ointments containing, for example, up to 10% by weight of the
active compound, soft and hard gelatin capsules, sterile injectable
solutions, and sterile packaged powders. In certain embodiments,
the pharmaceutical composition is in the form of tablets.
[0226] As used herein, "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. Supplementary active
ingredients can also be incorporated into the compositions.
[0227] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as methyl
and propylhydroxy-benzoates; sweetening agents; and flavoring
agents.
[0228] The compositions that include at least one compound of any
of the formulae described herein or a pharmaceutically acceptable
salt, isomer, prodrug, or solvate thereof, can be formulated so as
to provide quick, sustained or delayed release of the active
ingredient after administration to the subject by employing
procedures known in the art. Controlled release drug delivery
systems for oral administration include osmotic pump systems and
dissolutional systems containing polymer-coated reservoirs or
drug-polymer matrix formulations. Examples of controlled release
systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;
4,902,514; and 5,616,345. Another formulation for use in the
methods of the present invention employs transdermal delivery
devices ("patches"). Such transdermal patches may be used to
provide continuous or discontinuous infusion of the compounds
described herein in controlled amounts. The construction and use of
transdermal patches for the delivery of pharmaceutical agents is
well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252,
4,992,445 and 5,001,139. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0229] For preparing solid compositions such as tablets, the
principal active ingredient may be mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of any of the above formulae or a
pharmaceutically acceptable salt, prodrug, or solvate thereof. When
referring to these preformulation compositions as homogeneous, the
active ingredient may be dispersed evenly throughout the
composition so that the composition may be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules.
[0230] The tablets or pills of the compounds described herein may
be coated or otherwise compounded to provide a dosage form
affording the advantage of prolonged action, or to protect from the
acid conditions of the stomach. For example, the tablet or pill can
include an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer that serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0231] Compositions for inhalation or insufflation may include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. In other embodiments,
compositions in pharmaceutically acceptable solvents may be
nebulized by use of inert gases. Nebulized solutions may be inhaled
directly from the nebulizing device or the nebulizing device may be
attached to a facemask tent, or intermittent positive pressure
breathing machine. Solution, suspension, or powder compositions may
be administered, preferably orally or nasally, from devices that
deliver the formulation in an appropriate manner.
Dosing
[0232] The specific dose level of a compound of the formulae
described herein for any particular subject will depend upon a
variety of factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, route of administration, and rate of excretion,
drug combination and the severity of the particular disease in the
subject undergoing therapy. For example, a dosage may be expressed
as a number of milligrams of a compound of the formula per kilogram
of the subject's body weight (mg/kg). Dosages of between about 0.01
and 200 mg/kg may be appropriate. In some embodiments, about 0.01
and 150 mg/kg may be appropriate. In other embodiments a dosage of
between 0.05 and 100 mg/kg may be appropriate. Normalizing
according to the subject's body weight is particularly useful when
adjusting dosages between subjects of widely disparate size, such
as occurs when using the drug in both children and adult humans or
when converting an effective dosage in a non-human subject such as
dog to a dosage suitable for a human subject.
[0233] The daily dosage may also be described as a total amount of
a compound of the formulae administered per dose or per day. Daily
dosage of a compound may be between about 1 mg and 2,000 mg,
between about 1,000 to 2,000 mg/day, between about 1 to 1,000
mg/day, between about 1 to 500 mg/day, between about 100 to 150
mg/day, between about 1 to 100 mg/day, between about between about
1 to 50 mg/day, between about 50 to 100 mg/day, between about 100
to 125 mg/day, between about 100 to 150 mg/day, between about 100
to 175 mg/day, between about 100 to 200 mg/day, between about 100
to 225 mg/day, between about 100 to 250 mg/day, between about 100
to 350 mg/day, between about 100 to 400 mg/day, between about 100
to 450 mg/day, or between about 100 to 500 mg/day.
[0234] When administered orally, the total daily dosage for a human
subject may be between 1 mg and 1,000 mg/day, between about 1 to
100 mg/day, between about 1 to 50 mg/day, between about 50 to 100
mg/day, between 50 to 300 mg/day, between 50 to 200 mg/day, between
75 to 200 mg/day, between 75 to 150 mg/day, between 100 to 200
mg/day, between about 200 to 300 mg/day, between about 300 to 400
mg/day, between about 400 to 500 mg/day, between about 100 to 150
mg/day, between about 150 to 200 mg/day, between about 200 to 250
mg/day, between about 75 to 150 mg/day, or between about 150 to 300
mg/day.
[0235] The compounds of the present application or the compositions
thereof may be administered once, twice, three, or four times
daily, using any suitable mode described above. Also,
administration or treatment with the compounds according to any of
the formulae described herein may be continued for a number of
days; for example, commonly treatment would continue for at least 7
days, 14 days, or 28 days, for one cycle of treatment. In some
treatment, the compound or the composition thereof is administered
continuously, i.e. every day. Treatment cycles are well known in
cancer chemotherapy, and are frequently alternated with resting
periods of about 1 to 28 days, commonly about 7 days or about 14
days, between cycles. The treatment cycles, in other embodiments,
may also be continuous.
[0236] In a particular embodiment, the method comprises
administering to the subject an initial daily dose of about 1 to
500 mg of a compound of the above formula and increasing the dose
by increments until clinical efficacy is achieved. Increments of
about 1, 5, 10, 25, 50, 75, or 100 mg can be used to increase the
dose. The dosage can be increased daily, every other day, twice per
week, or once per week.
Synthesis of the Compounds
[0237] The compounds of the present application may be prepared
using the methods disclosed herein and routine modifications
thereof, which will be apparent given the disclosure herein and
methods well known in the art. Conventional and well-known
synthetic methods may be used in addition to the teachings herein.
The synthesis of typical compounds described herein may be
accomplished as described in the following examples. If available,
reagents may be purchased commercially, e.g., from Sigma Aldrich or
other chemical suppliers. In general, compounds described herein
are typically stable and isolatable at room temperature and
pressure.
General Synthesis
[0238] Typical embodiments of compounds described herein may be
synthesized using the general reaction schemes described below. It
will be apparent given the description herein that the general
schemes may be altered by substitution of the starting materials
with other materials having similar structures to result in
products that are correspondingly different. Descriptions of
syntheses follow to provide numerous examples of how the starting
materials may vary to provide corresponding products. Given a
desired product for which the substituent groups are defined, the
necessary starting materials generally may be determined by
inspection. Starting materials are typically obtained from
commercial sources or synthesized using published methods. For
synthesizing compounds which are embodiments described in the
present disclosure, inspection of the structure of the compound to
be synthesized will provide the identity of each substituent group.
The identity of the final product will generally render apparent
the identity of the necessary starting materials by a simple
process of inspection, given the examples herein.
Synthetic Reaction Parameters
[0239] The terms "solvent", "inert organic solvent", or "inert
solvent" refer to a solvent inert under the conditions of the
reaction being described in conjunction therewith (including, for
example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"),
dimethylformamide ("DMF"), chloroform, methylene chloride (or
dichloromethane), diethyl ether, methanol, and the like). Unless
specified to the contrary, the solvents used in the reactions of
the present invention are inert organic solvents, and the reactions
are carried out under an inert gas, preferably nitrogen or
argon.
[0240] The compounds of formula (IM) may be prepared using the
method similar to the Reaction Scheme I shown below:
##STR00190## ##STR00191##
Step 1--Preparation of a Compound of Formula (1)
[0241] The compounds of formula (1) can be made by combining
compounds (A) and (B). Compounds (A) and (B) are commercially
available or can be made by methods known in the art. With respect
to compound (A), Y.sup.1 is Cl, Br or neopentylglycolatoboron. With
respect to compound (B), R.sup.30 and R.sup.31 are independently
selected from R.sup.103 or B(OH).sub.2; and, X.sup.6 and X.sup.7
are independently selected from N and CR.sup.103 wherein R.sup.103
is as defined above. Compounds (A) and (B) can be mixed in the
presence of a catalyst such as
tetrakis(triphenylphosphine)palladium(0) and a base such as
potassium phosphate tribasic in a suitable solvent such as a
mixture of dioxane and water. After further stirring at a
temperature between 70 and 110.degree. C. for between 1 and 24
hours, the reaction mixture is allowed to cool to room temperature.
To extract the compound of formula (1), an organic solvent such as
ethyl acetate may be added, followed by washing with water and
brine. The organic phase can be concentrated to obtain the compound
of formula (1). The compound of formula (1) may be purified by any
suitable methods known in the art such as chromatography on silica
gel, trituration, precipitation or crystallization.
Step 2--Preparation of a Compound of Formula (2)
[0242] The compounds of formula (2) can be made by combining
compounds (1) and (C). Compound (C) is commercially available or
can be made by methods known in the art. With respect to compound
(C), (R.sup.1).sub.n and (R.sup.5).sub.s is as defined herein.
Compounds (1) and (C) can be mixed in the presence of a catalyst
such as palladium(II) acetate, a phosphine ligand such as
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine,
and a base such as potassium phosphate in a neutral solvent such as
toluene. The reaction is carried out at a temperature between 70
and 120.degree. C. for between 4 and 72 hours or until the reaction
is complete. Upon completion, the solvent is removed under reduced
pressure and the compound of formula (2) may be purified by any
suitable methods known in the art such as chromatography on silica
gel, trituration, precipitation or crystallization.
Step 3--Preparation of a Compound of Formula (3)
[0243] The compounds of formula (3) can be made by combining
compounds (2) and (D). Compound (D) is commercially available or
can be made by methods known in the art. With respect to compound
(D), R.sup.2 is as defined herein. Compounds (2) and (D) can be
mixed in the presence of a reducing agent such as sodium dithionite
in a solvent such as a mixture of dimethylsulfoxide and ethanol.
The reaction is carried out at a temperature between 30 and
120.degree. C. for between 4 and 72 hours or until the reaction is
complete. The reaction mixture is then partitioned between water
and an organic solvent such as ethyl acetate or methylene chloride,
followed by washing with water and brine. The organic phase can be
concentrated to obtain the compound of formula (3). The compound of
formula (3) may be purified by any suitable methods known in the
art such as chromatography on silica gel, trituration,
precipitation or crystallization.
Step 4--Preparation of a Compound of Formula (4)
[0244] The compounds of formula (4) may be prepared by hydrolysis
of the compounds of formula (3) by standard methods. A compound of
formula (3) is dissolved or slurried in a solvent such as
tetrahydrofuran or dioxane and lithium hydroxide may be added
either as a solution in water or with some water. The reaction is
carried out at ambient temperature for between 1 and 24 hours or
until the reaction is complete. The reaction is then acidified with
an acid such as hydrochloric acid and the solvent is removed under
reduced pressure to give a compound of formula (4).
Step 5--Preparation of a Compound of Formula (5)
[0245] The compounds of formula (5) may be prepared by amidation of
the compounds of formula (4) by standard methods. A compound of
formula (4) may be reacted with ammonium chloride in the presence
of hydroxybenzotriazole (HOBt), a base such as triethylamine or
diisopropylethylamine, and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC)
in a solvent such as dimethylformamide. The reaction is carried out
at a temperature between ambient temperature and 60.degree. C. for
between 2 and 96 hours or until the reaction is complete. To
extract the compound of formula (5), an organic solvent such as
ethyl acetate may be added, followed by washing with water and
brine. The organic phase can be concentrated under reduced pressure
to obtain the compound of formula (5). Alternatively, the compound
of formula (5) may precipitate with the addition of water and may
be recovered by filtration. The compound of formula (5) may be
purified by any suitable methods known in the art such as
chromatography on silica gel, preparative HPLC, trituration,
precipitation or crystallization.
Step 6--Preparation of a Compound of Formula (IM)
[0246] The compounds of formula (IM) can be made from the compounds
of formula (5) by a two-step procedure. A compound of formula (5)
may be reacted with a large excess of an appropriate reagent such
as 1,1-dimethoxy-N,N-dimethylethanamine or
1,1-dimethoxy-N,N-dimethylmethanamine at a temperature between
ambient temperature and 140.degree. C. for between 0.5 and 24 hours
or until the reaction is complete. The reagent is removed under
reduced pressure and the residue can be dissolved in acetic acid
followed by addition of hydrazine. The reaction is stirred at a
temperature between ambient temperature and 100.degree. C. for
between 0.5 and 24 hours or until the reaction is complete. The
solvent is removed under reduced pressure and the compound of
formula (IM) can be dissolved in an organic solvent such as ethyl
acetate, followed by washing with a solution of saturated sodium
bicarbonate and brine. The organic phase is concentrated under
reduced pressure to obtain the compound of formula (IM). The
compound of formula (IM) may be purified by any suitable methods
known in the art such as chromatography on silica gel, preparative
HPLC, trituration, precipitation or crystallization.
[0247] If protecting groups are present on the compound of formula
(IM) at this point, they may be removed by appropriate methods. For
example, Boc or THP groups may be removed by treatment with an acid
such as trifluoroacetic acid in a solvent such as methylene
chloride. The compound of formula (IM) may be purified by any
suitable methods known in the art such as chromatography on silica
gel, preparative HPLC, trituration, precipitation or
crystallization.
[0248] If the compound of formula (IM) is a mixture of
atropisomers, the isomers may be separated using a chiral
chromatography method. The solvents and chromatography column used
will depend on the specific compound being separated, but normal
phase, reverse phase or supercritical fluid chromatography may be
used.
[0249] Alternatively, compounds of formula (IM) can be made as
shown in Reaction Scheme 2.
##STR00192## ##STR00193##
Step 1--Preparation of a Compound of Formula (6)
[0250] The compounds of formula (6) can be made by combining ethyl
3-amino-2-nitrobenzoate with the compounds (C). Ethyl
3-amino-2-nitrobenzoate is commercially available or can be made by
methods known in the art. Compound (C) is commercially available or
can be made by methods known in the art. With respect to compound
(C), (R.sup.1).sub.n and (R.sup.5).sub.s is as defined herein.
Ethyl 3-amino-2-nitrobenzoate and compound (C) can be mixed in the
presence of a base such as cesium carbonate in a suitable solvent
such as dimethylformamide After further stirring at a temperature
between 70 and 130.degree. C. for between 2 and 48 hours, the
reaction mixture is allowed to cool to room temperature. To extract
the compound of formula (6), an organic solvent such as ethyl
acetate may be added, followed by washing with water and brine. The
organic phase can be concentrated under reduced pressure to obtain
the compound of formula (6). The compound of formula (6) may be
purified by any suitable methods known in the art such as
chromatography on silica gel, trituration, precipitation or
crystallization.
Step 2--Preparation of a Compound of Formula (7)
[0251] The compounds of formula (7) can be made by reduction of the
nitro group of the compounds of formula (6) using standard methods.
A reducing agent such as zinc dust can be added to a solution of a
compound of formula (6) in a suitable solvent such as acetic acid.
After further stirring at ambient temperature for between 0.5 and
24 hours, the reaction mixture can be filtered and the solvent can
be removed under reduced pressure. The compound of formula (7) can
be dissolved in an organic solvent such as ethyl acetate and washed
with a solution of sodium bicarbonate, water and brine. The organic
phase can be concentrated under reduced pressure to obtain the
compound of formula (7). The compound of formula (7) may be
purified by any suitable methods known in the art such as
chromatography on silica gel, trituration, precipitation or
crystallization.
Step 3--Preparation of a Compound of Formula (8)
[0252] The compounds of formula (8) can be made by bromination of
the compounds (7) using standard methods. A brominating agent such
as bromine can be added to a solution of a compound of formula (7)
in a suitable solvent such as dichloromethane. After further
stirring at a temperature between 0 and 40.degree. C. for between
0.5 and 24 hours, the reaction mixture can be quenched with a
reducing agent such as sodium thiosulfate. The mixture can then be
diluted with an organic solvent such as ethyl acetate and washed
with a solution of sodium carbonate, water and brine. The organic
phase can be concentrated under reduced pressure to obtain the
compound of formula (8). The compound of formula (8) may be
purified by any suitable methods known in the art such as
chromatography on silica gel, trituration, precipitation or
crystallization.
Step 4--Preparation of a Compound of Formula (9)
[0253] The compounds of formula (9) can be made by combining the
compounds (8) with an acid anhydride (E). Compound (E) is
commercially available or can be made by methods known in the art.
With respect to compound (E), R.sup.2 is as defined herein. A
solution of a compound of formula (8) and an excess of an acid
anhydride (E) in a solvent such as acetic acid can be stirred at a
temperature between 80 and 140.degree. C. for between 1 and 24
hours. The solvent can then be removed under reduced. The compound
of formula (9) can be dissolved in an organic solvent such as ethyl
acetate and washed with a solution of sodium bicarbonate, water and
brine. The organic phase can be concentrated under reduced pressure
to obtain the compound of formula (9). The compound of formula (9)
may be purified by any suitable methods known in the art such as
chromatography on silica gel, trituration, precipitation or
crystallization.
Step 5--Preparation of a Compound of Formula (10)
[0254] The compounds of formula (10) can be made by combining the
compounds (9) with bis(neopentyl glycolato)diboron. A compound of
formula (9) and bis(neopentyl glycolato)diboron can be mixed in the
presence of a catalyst such as
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
(complex with dichloromethane) and a base such as potassium acetate
in a suitable solvent such as dioxane. After further stirring at a
temperature between 70 and 120.degree. C. for between 1 and 48
hours, the reaction mixture is allowed to cool to room temperature.
After filtration and concentration under reduced pressure, the
compound of formula (10) may be purified by any suitable methods
known in the art such as chromatography on silica gel, trituration,
precipitation or crystallization.
Step 6--Preparation of a Compound of Formula (11)
[0255] The compounds of formula (11) can be made by combining
compounds (10) and (B). Compound (B) is commercially available or
can be made by methods known in the art. With respect to compound
(B), X.sup.6, X.sup.7, and R.sup.103 are as defined herein and
Y.sup.2 is Br or I. Compounds (10) and (B) can be mixed in the
presence of a catalyst such as
tetrakis(triphenylphosphine)palladium(0) and a base such as
potassium phosphate tribasic in a suitable solvent such as a
mixture of dioxane and water. After further stirring at a
temperature between 70 and 110.degree. C. for between 1 and 24
hours, the reaction mixture is allowed to cool to room temperature.
To extract the compound of formula (11), an organic solvent such as
ethyl acetate may be added, followed by washing with water and
brine. The organic phase can be concentrated under reduced pressure
to obtain the compound of formula (11). The compound of formula
(11) may be purified by any suitable methods known in the art such
as chromatography on silica gel, trituration, precipitation or
crystallization.
Step 7--Preparation of a Compound of Formula (4) from a Compound of
Formula (11)
[0256] The compounds of formula (4) may be prepared by hydrolysis
of the compounds of formula (11) by standard methods. A compound of
formula (11) is dissolved or slurred in a solvent such as
tetrahydrofuran or dioxane and lithium hydroxide may be added
either as a solution in water or with some water. The reaction is
carried out at ambient temperature for between 1 and 24 hours or
until the reaction is complete. The reaction is then acidified with
an acid such as hydrochloric acid and the solvent is removed under
reduced pressure to give a compound of formula (4).
[0257] Alternatively, compounds of formula (IM) can be made as
shown in Reaction Scheme 3.
##STR00194## ##STR00195##
Step 1--Preparation of a Compound of Formula (12)
[0258] The compounds of formula (12) can be made by combining the
compounds (8) and (F). Compound (8) is made as described is
Reaction Scheme 2. Compound (F) is commercially available or can be
made by methods known in the art. With respect to compound (F),
R.sup.2 is as defined herein. A solution of compound (8) in an
excess of compound (F) can be stirred at a temperature between 60
and 140.degree. C. for between 1 and 48 hours. The solvent can then
be removed under reduced pressure. The compound of formula (12) may
be purified by any suitable methods known in the art such as
chromatography on silica gel, trituration, precipitation or
crystallization.
Step 2--Preparation of a Compound of Formula (13)
[0259] The compounds of formula (13) may be prepared by hydrolysis
of the compounds of formula (12) by standard methods. A compound of
formula (12) is dissolved or slurred in a solvent such as
tetrahydrofuran or dioxane and lithium hydroxide may be added
either as a solution in water or with some water. The reaction is
carried out at ambient temperature for between 1 and 24 hours or
until the reaction is complete. The reaction is then acidified with
an acid such as hydrochloric acid and the solvent is removed under
reduced pressure to give a compound of formula (13).
Step 3--Preparation of a Compound of Formula (14)
[0260] The compounds of formula (14) may be prepared by amidation
of the compounds of formula (13) by standard methods. A compound of
formula (13) may be reacted with ammonium chloride in the presence
of hydroxybenzotriazole (HOBt), a base such as triethylamine or
diisopropylethylamine, and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC)
in a solvent such as dimethylformamide. The reaction is carried out
at a temperature between ambient temperature and 60.degree. C. for
between 12 and 96 hours or until the reaction is complete. To
extract the compound of formula (14), an organic solvent such as
ethyl acetate may be added, followed by washing with water and
brine. The organic phase can be concentrated under reduced pressure
to obtain the compound of formula (14). Alternatively, the compound
of formula (14) may precipitate with the addition of water. The
compound of formula (14) may be purified by any suitable methods
known in the art such as chromatography on silica gel, trituration,
precipitation or crystallization.
Step 4--Preparation of a Compound of Formula (15)
[0261] The compounds of formula (15) can be made by combining the
compounds (14) and bis(neopentyl glycolato)diboron. A compound of
formula (14) and bis(neopentyl glycolato)diboron can be mixed in
the presence of a catalyst such as
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
(complex with dichloromethane) and a base such as potassium acetate
in a suitable solvent such as dioxane. After further stirring at a
temperature between 70 and 120.degree. C. for between 5 and 48
hours, the reaction mixture is allowed to cool to room temperature.
If the compound of formula (15) precipitate upon cooling, the
material can be recovered by filtration, washing with water and
drying under vacuum. Alternatively, to extract the compound of
formula (15), an organic solvent such as ethyl acetate may be
added, followed by washing with water and brine. The organic phase
can be concentrated under reduced pressure to obtain the compound
of formula (15). The compound of formula (15) may be purified by
any suitable methods known in the art such as chromatography on
silica gel, trituration, precipitation or crystallization.
Step 5--Preparation of a Compound of Formula (5) from a Compound of
Formula (15)
[0262] The compounds of formula (5) can be made by combining
compounds (15) and (B). Compound (B) is commercially available or
can be made by methods known in the art. With respect to compound
(B), X.sup.6, X.sup.7, R.sup.30 and R.sup.31 are as defined herein
and Y.sup.2 is Br or I. Compounds (15) and (B) can be mixed in the
presence of a catalyst such
tetrakis(triphenylphosphine)palladium(0) and a base such as
potassium phosphate tribasic in a suitable solvent such as a
mixture of dioxane and water. After further stirring at a
temperature between 70 and 110.degree. C. for between 1 and 24
hours, the reaction mixture is allowed to cool to room temperature.
To extract the compound of formula (5), an organic solvent such as
ethyl acetate may be added, followed by washing with water and
brine. The organic phase can be concentrated under reduced pressure
to obtain the compound of formula (5). The compound of formula (5)
may be purified by any suitable methods known in the art such as
chromatography on silica gel, preparative HPLC, trituration,
precipitation or crystallization.
Preparation of the Compounds of Formula (4) According to Reaction
Scheme 1
A. Preparation of Methyl
3-amino-2-nitro-5-(pyridin-4-yl)benzoate
##STR00196##
[0264] Tetrakis(triphenylphosphine)palladium(0) (2.50 g, 2.17 mmol)
was added to a solution of methyl 3-amino-5-chloro-2-nitrobenzoate
(5.0 g, 21.7 mmol), pyridin-4-ylboronic acid (2.7 g, 21.7 mmol),
and potassium phosphate tribasic (13.8 g, 65 mmol) in THF (200 mL)
and water (50 mL). Nitrogen was bubbled for 10 minutes, the vessel
was sealed, and the reaction mixture was stirred at 90.degree. C.
for 16 hours. Upon cooling, the reaction mixture was partitioned
between ethyl acetate and water. The organic phase was washed with
brine, dried with magnesium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography eluting with 5 to 100% of (5% methanol in
ethyl acetate) in hexane to afford methyl
3-amino-2-nitro-5-(pyridin-4-yl)benzoate.
B. Preparation of Methyl
3-amino-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate
##STR00197##
[0266] Palladium(II) acetate (0.49 g, 2.17 mmol) was added to a
solution of methyl 3-amino-5-chloro-2-nitrobenzoate (10 g, 43.4
mmol), bis(neopentyl glycolato)diboron (19.6 g, 86.7 mmol),
1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ium chloride (1.8 g,
4.3 mmol), and potassium acetate (10.6 g, 108 mmol) in THF (400
mL). Nitrogen was bubbled for 10 minutes, the flask was closed with
a septum, and the reaction mixture was stirred at 50.degree. C. for
72 hours. The reaction mixture was cooled to ambient temperature
and the solid was filtered. The filtrate was dry loaded onto silica
gel and purified by silica gel column chromatography eluting with 5
to 70% ethyl acetate in hexane to afford methyl
3-amino-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrobenzoate.
ES/MS m/z=263.2 (ArB(OH).sub.2+Na).sup.+.
[0267] Tetrakis(triphenylphosphine)palladium(0) (1.91 mg, 1.66
mmol) was added to a solution of methyl
3-amino-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrobenzoate
(6.1 g, 19.9 mmol), 2,3-difluoro-4-iodopyridine (4.0 g, 16.6 mmol),
and potassium phosphate tribasic (10.6 g, 49.8 mmol) in dioxane (80
mL) and water (20 mL). Nitrogen was bubbled for 10 minutes and the
reaction mixture was stirred at 80.degree. C. for 10 hours. Upon
cooling, the reaction mixture was partitioned between ethyl acetate
and water. The organic phase was washed with brine, dried with
magnesium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography eluting with 5 to 70% of (5% methanol in ethyl
acetate) in hexane to afford methyl
3-amino-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate. ES/MS
m/z=310.2 (M+H).sup.+.
[0268] The following compounds were prepared using a similar
procedure: [0269] methyl
3-amino-5-(3-fluoropyridin-4-yl)-2-nitrobenzoate [0270] methyl
3-amino-5-(2-methylpyridin-4-yl)-2-nitrobenzoate [0271] methyl
3-amino-5-(2,5-difluoropyridin-4-yl)-2-nitrobenzoate [0272] methyl
3-amino-5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-nitrobenzoate
[0273] methyl
3-amino-5-(2-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2-nitrobenzoa-
te [0274] methyl
3-amino-5-(2,6-bis((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2-nitrob-
enzoate [0275] methyl
3-amino-5-(6-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2-nitrobenzoa-
te [0276] methyl
3-amino-2-nitro-5-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)benzoate
[0277] methyl
3-amino-5-(2,5-difluoropyridin-4-yl)-2-nitrobenzoate
C. Preparation of Methyl
3-((8-chloroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenz-
oate
##STR00198##
[0279] To a solution of 4,8-dichloroquinoline (384 mg, 1.94 mmol)
and methyl 3-amino-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate
(500 mg, 1.62 mmol) in toluene (8.0 mL) was added XPhos (185 mg,
0.39 mmol), palladium acetate (29 mg, 0.13 mmol) and potassium
phosphate tribasic (686 mg, 3.23 mmol). Nitrogen was bubbled for 5
min. The vessel was closed and the reaction mixture was stirred at
100.degree. C. for overnight. Upon cooling, the reaction mixture
was filtered. The filtrate was dry loaded onto silica gel and
purified using silica gel chromatography eluting with 5 to 100% of
(10% methanol in ethyl acetate) in hexane to afford methyl
3-((8-chloroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenz-
oate. ES/MS m/z=471.1 (M+H).sup.+.
[0280] The following compounds were prepared using a similar
procedure: [0281] methyl
3-((8-chloroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate
[0282] methyl
3-((5,8-difluoroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzo-
ate [0283] methyl
3-((5,8-dichloroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate
[0284] methyl
3-((5-fluoroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate
[0285] methyl
3-((5-methylquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate
[0286] methyl
3-((8-chloro-2-methylquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoat-
e [0287] methyl
3-((2-methylquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate
[0288] methyl
3-((8-chloro-5-fluoroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)-
benzoate [0289] methyl
3-((8-chloroquinolin-4-yl)amino)-5-(3-fluoropyridin-4-yl)-2-nitrobenzoate
[0290] methyl
3-((8-chloroquinolin-4-yl)amino)-5-(2-methylpyridin-4-yl)-2-nitrobenzoate
[0291] methyl
5-(2,5-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitro-
benzoate [0292] methyl
5-(2,3-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitro-
benzoate [0293] methyl
5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((5,8-difluoroquinoli-
n-4-yl)amino)-2-nitrobenzoate [0294] methyl
5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((8-chloroquinolin-4--
yl)amino)-2-nitrobenzoate [0295] methyl
5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((8-chloro-5-fluoroqu-
inolin-4-yl)amino)-2-nitrobenzoate [0296] methyl
5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((7-fluoroquinolin-4--
yl)amino)-2-nitrobenzoate [0297] methyl
5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((5-fluoroquinolin-4--
yl)amino)-2-nitrobenzoate [0298] methyl
5-(2-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-3-((8-chloroquinolin--
4-yl)amino)-2-nitrobenzoate [0299] methyl
5-(2,6-bis((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-3-((8-chloroquin-
olin-4-yl)amino)-2-nitrobenzoate [0300] methyl
5-(6-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-3-((8-chloroquinolin--
4-yl)amino)-2-nitrobenzoate [0301] methyl
3-((8-chloroquinolin-4-yl)amino)-2-nitro-5-(9-(tetrahydro-2H-pyran-2-yl)--
9H-purin-6-yl)benzoate [0302] methyl
5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((8-fluoroquinolin-4--
yl)amino)-2-nitrobenzoate [0303] methyl
5-(2,3-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitro-
benzoate [0304] methyl
3-((8-chloro-5-fluoroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2--
nitrobenzoate [0305] methyl
5-(2,3-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitro-
benzoate [0306] methyl
5-(2,5-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitro-
benzoate [0307] methyl
5-(2,3-difluoropyridin-4-yl)-3-((8-fluoroquinolin-4-yl)amino)-2-nitrobenz-
oate [0308] methyl
3-((8-chloro-3-methylquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2--
nitrobenzoate [0309] methyl
3-((3-chloro-8-fluoroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2--
nitrobenzoate [0310] methyl
5-(2,3-difluoropyridin-4-yl)-3-((5-fluoroquinolin-4-yl)amino)-2-nitrobenz-
oate [0311] methyl
3-((5-chloro-8-fluoroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2--
nitrobenzoate
D. Preparation of a Methyl
1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylate
##STR00199##
[0313] Acetaldehyde (0.15 mL, 2.74 mmol) was added to a solution of
methyl
3-((8-chloroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenz-
oate (215 mg, 0.46 mmol) and sodium dithionite (281 mg, 1.37 mmol)
in ethanol (2.5 mL) and DMSO (2.5 mL). The reaction vessel was
closed and the reaction mixture was stirred at 80.degree. C. for
overnight. Upon cooling, the reaction mixture was partitioned
between ethyl acetate and water. The organic phase was washed with
brine, dried with magnesium sulfate, filtered, and concentrated
under reduced pressure to afford methyl
1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-
-benzo[d]imidazole-4-carboxylate. ES/MS m/z=465.2 (M+H).sup.+.
[0314] The following compounds were prepared using a similar
procedure: [0315] methyl
1-(8-chloroquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxy-
late [0316] methyl
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidaz-
ole-4-carboxylate [0317] methyl
1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidaz-
ole-4-carboxylate [0318] methyl
1-(5-fluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole--
4-carboxylate [0319] methyl
2-methyl-1-(5-methylquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole--
4-carboxylate [0320] methyl
1-(8-chloro-2-methylquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]i-
midazole-4-carboxylate [0321] methyl
2-methyl-1-(2-methylquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole--
4-carboxylate [0322] methyl
1-(8-chloroquinolin-4-yl)-2-(oxetan-3-yl)-6-(pyridin-4-yl)-1H-benzo[d]imi-
dazole-4-carboxylate [0323] methyl
1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]i-
midazole-4-carboxylate [0324] methyl
1-(8-chloroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole--
4-carboxylate [0325] methyl
1-(8-chloroquinolin-4-yl)-6-(3-fluoropyridin-4-yl)-2-methyl-1H-benzo[d]im-
idazole-4-carboxylate [0326] methyl
1-(8-chloroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]im-
idazole-4-carboxylate [0327] methyl
6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylate [0328] methyl
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylate [0329] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-
-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0330] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-y-
l)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0331] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroqui-
nolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0332]
methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-ethyl-1-(7-fluoroquin-
olin-4-yl)-1H-benzo[d]imidazole-4-carboxylate [0333] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(7-fluoroquinolin-4-y-
l)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0334] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-ethyl-1-(5-fluoroquin-
olin-4-yl)-1H-benzo[d]imidazole-4-carboxylate [0335] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5-fluoroquinolin-4-y-
l)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0336] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinolin-4-
-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0337] methyl
6-(2,6-bis((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquino-
lin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0338] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-y-
l)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0339] methyl
1-(8-chloroquinolin-4-yl)-2-methyl-6-(9-(tetrahydro-2H-pyran-2-yl)-9H-pur-
in-6-yl)-1H-benzo[d]imidazole-4-carboxylate [0340] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-cyclopropyl-1-(8-fluo-
roquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate [0341] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-fluoroquinolin-4-y-
l)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0342] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroqui-
nolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylate [0343]
methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroqui-
nolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylate [0344]
methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroqui-
nolin-4-yl)-2-isopropyl-1H-benzo[d]imidazole-4-carboxylate [0345]
methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroqui-
nolin-4-yl)-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxylate
[0346] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-cyclopropyl-1--
(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate
[0347] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroq-
uinolin-4-yl)-2-ethyl-1H-benzo[d]imidazole-4-carboxylate [0348]
methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-(cyclopropylmethyl)-1-
-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate
[0349] methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroq-
uinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylate [0350]
methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-y-
l)-2-(cyclopropylmethyl)-1H-benzo[d]imidazole-4-carboxylate [0351]
methyl
6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-y-
l)-2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylate [0352] methyl
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-be-
nzo[d]imidazole-4-carboxylate [0353] methyl
1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-
-yl)-1H-benzo[d]imidazole-4-carboxylate [0354] methyl
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylate [0355] methyl
6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylate [0356] methyl
1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-b-
enzo[d]imidazole-4-carboxylate [0357] methyl
2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)--
1H-benzo[d]imidazole-4-carboxylate [0358] methyl
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate [0359] methyl
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-propyl--
1H-benzo[d]imidazole-4-carboxylate [0360] methyl
6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylate [0361] methyl
6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-propyl-1H-benzo[-
d]imidazole-4-carboxylate [0362] methyl
2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-1H-b-
enzo[d]imidazole-4-carboxylate [0363] methyl
1-(8-chloro-3-methylquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate [0364] methyl
1-(3-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate [0365] methyl
6-(2,3-difluoropyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylate [0366] methyl
6-(2,3-difluoropyridin-4-yl)-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d-
]imidazole-4-carboxylate [0367] methyl
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-ben-
zo[d]imidazole-4-carboxylate [0368] methyl
2-(cyclopropylmethyl)-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinoli-
n-4-yl)-1H-benzo[d]imidazole-4-carboxylate [0369] methyl
1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate
E. Preparation of
1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylic Acid
##STR00200##
[0371] Aqueous 1M lithium hydroxide (1.0 mL) was added to a
solution of methyl
1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-
-benzo[d]imidazole-4-carboxylate (206 mg, 0.44 mmol) in THF (4 mL).
The reaction was stirred at ambient temperature for 1 hour. The
reaction mixture was acidified with 4N HCl in dioxane. The
resulting solution was concentrated to afford
1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylic acid which was used without further
purification for the next step. ES/MS m/z 451.10 (M+H).sup.+.
[0372] The following compounds were prepared using a similar
procedure: [0373]
1-(8-chloroquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4--
carboxylic acid [0374]
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidaz-
ole-4-carboxylic acid [0375]
1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidaz-
ole-4-carboxylic acid [0376]
1-(5-fluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole--
4-carboxylic acid [0377]
2-methyl-1-(5-methylquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole--
4-carboxylic acid [0378]
1-(8-chloro-2-methylquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]i-
midazole-4-carboxylic acid [0379]
2-methyl-1-(2-methylquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole--
4-carboxylic acid [0380]
1-(8-chloroquinolin-4-yl)-2-(oxetan-3-yl)-6-(pyridin-4-yl)-1H-benzo[d]imi-
dazole-4-carboxylic acid [0381]
1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]i-
midazole-4-carboxylic acid [0382]
1-(8-chloroquinolin-4-yl)-6-(3-fluoropyridin-4-yl)-2-methyl-1H-benzo[d]im-
idazole-4-carboxylic acid [0383]
1-(8-chloroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]im-
idazole-4-carboxylic acid [0384]
6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylic acid [0385]
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylic acid [0386]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4--
yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid [0387]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)--
2-methyl-1H-benzo[d]imidazole-4-carboxylic acid [0388]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinol-
in-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid [0389]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-ethyl-1-(7-fluoroquinoli-
n-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid [0390]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(7-fluoroquinolin-4-yl)--
2-methyl-1H-benzo[d]imidazole-4-carboxylic acid [0391]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-ethyl-1-(5-fluoroquinoli-
n-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid [0392]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5-fluoroquinolin-4-yl)--
2-methyl-1H-benzo[d]imidazole-4-carboxylic acid [0393]
6-(2,6-bis((tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinolin-
-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid [0394]
6-(6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinolin-4-yl-
)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid [0395]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-cyclopropyl-1-(8-fluoroq-
uinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid [0396]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-fluoroquinolin-4-yl)--
2-methyl-1H-benzo[d]imidazole-4-carboxylic acid [0397]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinol-
in-4-yl)-2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylic acid
[0398]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinol-
in-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylic acid [0399]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinol-
in-4-yl)-2-isopropyl-1H-benzo[d]imidazole-4-carboxylic acid [0400]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinol-
in-4-yl)-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid
[0401]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-cyclopropyl-1-(5,8-diflu-
oroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid [0402]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4--
yl)-2-ethyl-1H-benzo[d]imidazole-4-carboxylic acid [0403]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-(cyclopropylmethyl)-1-(5-
,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid
[0404]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4--
yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylic acid [0405]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)--
2-(cyclopropylmethyl)-1H-benzo[d]imidazole-4-carboxylic acid [0406]
6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)--
2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylic acid [0407]
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-be-
nzo[d]imidazole-4-carboxylic acid [0408]
1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-
-yl)-1H-benzo[d]imidazole-4-carboxylic acid [0409]
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylic acid [0410]
6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylic acid [0411]
1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-b-
enzo[d]imidazole-4-carboxylic acid [0412]
1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylic acid [0413]
2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)--
1H-benzo[d]imidazole-4-carboxylic acid [0414]
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid [0415]
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-propyl--
1H-benzo[d]imidazole-4-carboxylic acid [0416]
6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylic acid [0417]
6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-propyl-1H-benzo[-
d]imidazole-4-carboxylic acid [0418]
2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-1H-b-
enzo[d]imidazole-4-carboxylic acid [0419]
6-(2,3-difluoropyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylic acid [0420]
1-(8-chloro-3-methylquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid [0421]
1-(3-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid [0422]
6-(2,3-difluoropyridin-4-yl)-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d-
]imidazole-4-carboxylic acid [0423]
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-ben-
zo[d]imidazole-4-carboxylic acid [0424]
2-(cyclopropylmethyl)-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinoli-
n-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid [0425]
1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid
TABLE-US-00003 [0425] Example Name MS NMR 1 1-(8-chloroquinolin-
415.1 1H NMR (400 MHz, DMSO-d6) 4-yl)-2-methyl-6- .delta. 9.33 (d,
J = 4.5 Hz, 1H), 8.65 pyridin-4- (d, J = 5.5 Hz, 3H), 8.32 (s,
ylbenzimidazole-4- 1H), 8.10 (dd, J = 7.5, 1.2 Hz, carboxylic acid
1H), 8.03 (d, J = 4.5 Hz, 1H), 7.96 (s, 3H), 7.87 (s, 1H), 7.57
(dd, J = 8.4, 7.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 2.46 (s,
3H).
F. Preparation of
6-(2-aminopyrimidin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]i-
midazole-4-carboxamide
##STR00201##
[0427]
6-(2-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinoli-
n-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (17 mg,
0.032 mmol) was dissolved in dichloromethane (1.0 mL) and
trifluoroacetic acid (50 .mu.L, 0.64 mmol) was added. The reaction
mixture was stirred at ambient temperature for 1 hour, after which
the reaction was concentrated under reduced pressure. The resultant
was purified by HPLC eluting with 5-95% water/acetonitrile (0.1%
v/v trifluoroacetic acid). The appropriate fractions were pooled
and lyophilized to afford
6-(2-aminopyridimin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]i-
midazole-4-carboxamide as a 2,2,2-trifluoroacetic acid salt
(Example 2).
TABLE-US-00004 Example Name MS NMR 2 6-(2-amino- 431.1 1H NMR (400
MHz, DMSO-d6) pyrimidin- .delta. 9.37-9.33 (m, 1H), 8.72 (d,
4-yl)-1-(8- J = 1.6 Hz, 1H), 8.22 (dd, chloro- J = 5.5, 0.5 Hz,
1H), 8.11 (dd, quinolin-4-yl)- J = 7.5, 1.2 Hz, 1H), 8.05 (d,
2-methyl- J = 4.5 Hz, 1H), 7.97 (d, J = benzimidazole- 1.7 Hz, 1H),
7.63-7.55 (m, 1H), 4-carboxylic acid 7.35 (d, J = 8.4 Hz, 1H), 7.21
(d, J = 5.6 Hz, 1H), 7.06 (s, 2H), 2.46 (s, 3H). 3
1-(8-chloroquinolin- 456.1 1H NMR (400 MHz, DMSO-d6)
4-yl)-2-methyl-6- .delta. 9.63 (s, 1H), 9.38 (d, J = (9H-purin-6-
4.5 Hz, 1H), 8.82 (s, 1H), 8.61 yl)benzimidazole-4- (s, 1H), 8.56
(s, 1H), 8.16-8.11 carboxylic acid (m, 2H), 7.61 (dd, J = 8.5, 7.5
Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 2.51 (s, 3H).
G. Preparation of
6-(2-amino-3-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1-
H-benzo[d]imidazole-4-carboxylic
##STR00202##
[0429] Ammonium hydroxide (28-30% solution in water, 0.75 mL) was
added to a solution of crude
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylic acid (0.17 mmol) in DMSO (2.0 mL). The
reaction vessel was sealed and the reaction mixture was stirred at
100.degree. C. overnight. The excess ammonia was removed under
reduced pressure and the resulting solution was purified by HPLC
eluting with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic
acid). The appropriate fractions were pooled and lyophilized to
afford
6-(2-amino-3-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1-
H-benzo[d]imidazole-4-carboxylic acid as a 2,2,2-trifluoroacetic
acid salt (Example 4).
TABLE-US-00005 Example Name MS NMR 4 6-(2-amino-3- 450.1 1H NMR
(400 MHz, DMSO-d6) fluoro- .delta. 9.31(d, J = 4.5 Hz, 1H), 8.12
pyridin-4-yl)-1- (t, J = 1.5 Hz, 1H), 8.07 (d, (5,8-difluoro- J =
4.5 Hz, 1H), 7.78 (ddd, J = quinolin-4- 10.0, 8.8, 4.3 Hz, 1H),
7.73 (d, yl)-2-methyl- J = 6.0 Hz, 1H), 7.71 (s, 1H),
benzimidazole- 7.47 (ddd, J = 12.3, 8.8, 3.8 Hz, 4-carboxylic acid
1H), 6.82 (t, J = 5.8 Hz, 1H), 2.49 (s, 3H).
Preparation of the Compounds of Formula (4) According to Reaction
Scheme 2
A. Preparation of tert-butyl
4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate
##STR00203##
[0431] A suspension of 2,4-dichloroquinoline (6.4 g, 32.2 mmol),
tert-butyl piperazine-1-carboxylate (5.0 g, 26.8 mmol) and
diethylisopropylamine (6.5 mL, 38.0 mmol) was stirred in a sealed
at 100.degree. C. for 2 days. Upon cooling, the reaction mixture
was concentrated in vacuuo to afford material which was purified by
column chromatography on SiO2 eluting with EtOAc in hexanes (0-15%)
to afford tert-butyl
4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate (3.2 g, 34%).
ES/MS m/z=348.1 (M+H)+.
B. Preparation of
4-chloro-2-(1-trityl-1H-pyrazol-4-yl)quinoline
##STR00204##
[0433] A sealed tube was charged with 2,4-dichloroquinoline (1.0 g,
5.05 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazo-
le (2.2 g, 5.05 mmol), K.sub.3PO.sub.4 (3.2 g, 15.1 mmol) and
Pd(PPh.sub.3).sub.4 (0.58 g, 0.50 mmol) followed by dioxane (50 mL)
and water (12 mL). The reaction mixture was stirred at 90.degree.
C. for 3 h. Upon cooling, the reaction mixture was absorbed on SiO2
followed by purification on column chromatography on SiO2 eluting
with EtOAc in hexanes (0-100%) to afford
4-chloro-2-(1-trityl-1H-pyrazol-4-yl)quinoline (1.15 g, 48%). ES/MS
m/z=472.2 (M+H)+.
C. Preparation of ethyl
3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate
##STR00205##
[0435] To a cooled solution of 4-chloro-5,8-difluoroquinoline (171
g, 859.3 mmol) in DMF (1.7 L) were added ethyl
3-amino-2-nitrobenzoate (181.5 g, 859.3 mmol) and Cs.sub.2CO.sub.3
(614.4 g, 1890 mmol). The reaction mixture was stirred at
90.degree. C. for 18 hours. The reaction mixture was cooled down
and filtered through a pad of Celite. The filtrate was partitioned
between ethyl acetate and water. The organic phase was washed with
brine, dried with sodium sulfate, filtered, and concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography eluting with 30% ethyl acetate in petroleum
ether to afford ethyl
3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate. ES/MS
m/z=374.4 (M+H).sup.+.
[0436] The following compounds were prepared using a similar
procedure: [0437] ethyl
3-((5,8-dichloroquinolin-4-yl)amino)-2-nitrobenzoate [0438] ethyl
3-((5-chloroquinolin-4-yl)amino)-2-nitrobenzoate [0439] ethyl
3-((5-chloro-8-fluoroquinolin-4-yl)amino)-2-nitrobenzoate
D. Preparation of ethyl
3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate
##STR00206##
[0441] Palladium (II) acetate (103 mg, 0.46 mmol) was added to a
mixture of ethyl 3-amino-2-nitrobenzoate (1.2 g, 5.7 mmol),
4,8-dichloroquinoline (1.24 g, 6.3 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(653 mg, 1.37 mmol), and potassium phosphate (2.42 g, 11.4 mmol) in
toluene (23 mL). The resultant was degassed and stirred at
90.degree. C. for 16 hours. The reaction mixture was cooled to room
temperature and dry loaded onto silica gel and purified eluting
with 0 to 100% ethyl acetate in hexanes to afford the title
compound as a brown solid. ES/MS m/z=372.1 (M+H).sup.+. The
following compounds were prepared using a similar procedure: [0442]
ethyl 3-((5,7-difluoroquinolin-4-yl)amino)-2-nitrobenzoate [0443]
ethyl 3-((8-fluoroquinolin-4-yl)amino)-2-nitrobenzoate [0444] ethyl
3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate [0445] ethyl
3-((5-fluoroquinolin-4-yl)amino)-2-nitrobenzoate [0446] ethyl
3-((8-chloro-5-fluoroquinolin-4-yl)amino)-2-nitrobenzoate [0447]
tert-butyl
4-(4-((3-(ethoxycarbonyl)-2-nitrophenyl)amino)quinolin-2-yl)piperazine-1--
carboxylate [0448] ethyl
2-nitro-3-((2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)amino)benzoate
[0449] tert-butyl
4-(4-((2-nitrophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate
E. Preparation of a Compound of Formula (7) in which n=2,
(R.sup.1).sub.n=5,8-difluoro
##STR00207##
[0451] To a solution of ethyl
3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate (158 g, 423.49
mmol) in AcOH (1.3 L) and MeOH (320 mL) at 0.degree. C., Zn-dust
(166.1 g, 2541 mmol) was slowly added and the mixture was stirred
at ambient temperature for 1 hour. The reaction mixture was
filtered through a pad of Celite and evaporated under reduced
pressure. The resulting residue was suspended in DCM and washed
with an aqueous saturated solution of NaHCO.sub.3 followed brine.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give ethyl
2-amino-3-((5,8-difluoroquinolin-4-yl)amino)benzoate. ES/MS
m/z=344.0 (M+H).sup.+.
[0452] The following compounds were prepared using a similar
procedure: [0453] ethyl
2-amino-3-((5,7-difluoroquinolin-4-yl)amino)benzoate [0454] ethyl
2-amino-3-((5,8-dichloroquinolin-4-yl)amino)benzoate [0455] ethyl
2-amino-3-((5-chloro-8-fluoroquinolin-4-yl)amino)benzoate [0456]
ethyl 2-amino-3-((5-chloroquinolin-4-yl)amino)benzoate [0457] ethyl
2-amino-3-((8-fluoroquinolin-4-yl)amino)benzoate [0458] ethyl
2-amino-3-((8-chloroquinolin-4-yl)amino)benzoate [0459] ethyl
2-amino-3-((5-fluoroquinolin-4-yl)amino)benzoate [0460] ethyl
2-amino-3-((8-chloro-5-fluoroquinolin-4-yl)amino)benzoate [0461]
tert-butyl
4-(4-((2-amino-3-(ethoxycarbonyl)phenyl)amino)quinolin-2-yl)piperazine-1--
carboxylate [0462] ethyl
2-amino-3-((2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)amino)benzoate
[0463] tert-butyl
4-(4-((2-aminophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate
F. Preparation of Ethyl
2-amino-5-bromo-3-((5,8-difluoroquinolin-4-yl)amino)benzoate
##STR00208##
[0465] To a stirred solution of ethyl
2-amino-3-((5,8-difluoroquinolin-4-yl)amino)benzoate (135 g, 393
mmol) in DCM (2.7 L) at 0.degree. C., bromine (30.4 mL, 1180 mmol)
was added and the mixture was stirred at 0.degree. C. for 1 hour.
The reaction mixture was quenched with aqueous
Na.sub.2S.sub.2O.sub.3, diluted with DCM and washed with an aqueous
saturated solution of NaHCO.sub.3 followed by brine. The organic
layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure to give ethyl
2-amino-5-bromo-3-((5,8-difluoroquinolin-4-yl)amino)benzoate. ES/MS
m/z=422.0 (M+H).sup.+.
[0466] The following compounds were prepared using a similar
procedure: [0467] ethyl
2-amino-5-bromo-3-((5,7-difluoroquinolin-4-yl)amino)benzoate [0468]
ethyl 2-amino-5-bromo-3-((5,8-dichloroquinolin-4-yl)amino)benzoate
[0469] ethyl
2-amino-5-bromo-3-((5-chloro-8-fluoroquinolin-4-yl)amino)benzoate
[0470] ethyl
2-amino-5-bromo-3-((5-chloroquinolin-4-yl)amino)benzoate [0471]
ethyl 2-amino-5-bromo-3-((8-fluoroquinolin-4-yl)amino)benzoate
[0472] ethyl
2-amino-5-bromo-3-((8-chloroquinolin-4-yl)amino)benzoate [0473]
ethyl 2-amino-5-bromo-3-((5-fluoroquinolin-4-yl)amino)benzoate
[0474] ethyl
2-amino-5-bromo-3-((8-chloro-5-fluoroquinolin-4-yl)amino)benzoatete-
rt-butyl
4-(4-((2-amino-5-bromo-3-(ethoxycarbonyl)phenyl)amino)quinolin-2--
yl)piperazine-1-carboxylateethyl
2-amino-5-bromo-3-((2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)amino)benzo-
ate [0475] tert-butyl
4-(4-((2-amino-5-bromophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate
G. Preparation of Ethyl
6-bromo-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-car-
boxylate
##STR00209##
[0477] A solution of ethyl
2-amino-5-bromo-3-((5,8-difluoroquinolin-4-yl)amino)benzoate (103
g, 244 mmol) in Ac.sub.2O (515 mL) and AcOH (1 L) was refluxed for
18 hours. The reaction mixture was concentrated under reduced
pressure. The residue was diluted with ethyl acetate and washed
with an aqueous saturated solution of NaHCO.sub.3 followed by
brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure. The crude compound was
triturated with petroleum ether to give ethyl [0478]
6-bromo-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-car-
boxylate. ES/MS m/z=446.2 (M+H).sup.+.
[0479] The following compounds were prepared using a similar
procedure: [0480] ethyl
6-bromo-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-car-
boxylate [0481] ethyl
6-bromo-1-(5,8-dichloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-car-
boxylate [0482] ethyl
6-bromo-1-(5-chloro-8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole--
4-carboxylate [0483] ethyl
6-bromo-1-(5-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxy-
late [0484] ethyl
6-bromo-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxy-
late [0485] ethyl
6-bromo-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxy-
late [0486] ethyl
6-bromo-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxy-
late [0487] ethyl
6-bromo-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole--
4-carboxylate
H. Preparation of Ethyl
6-bromo-1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-1H-ben-
zo[d]imidazole-4-carboxylate
##STR00210##
[0489] A solution tert-butyl
4-(4-((2-amino-5-bromo-3-(ethoxycarbonyl)phenyl)amino)quinolin-2-yl)piper-
azine-1-carboxylate (2.29 g, 4.0 mmol) in trimethyl orthoformate
(30 mL) was refluxed for 30 minutes. The reaction mixture was
cooled to room temperature and dry loaded onto silica gel and
purified eluting with 0 to 100% ethyl acetate in hexanes to afford
the title compound as a brown solid. ES/MS m/z=580.1
(M+H).sup.+.
[0490] The following compounds were prepared using a similar
procedure: [0491] ethyl
6-bromo-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazol-
e-4-carboxylate [0492] tert-butyl
4-(4-(6-bromo-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxy-
late
I. Preparation of Ethyl
1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2--
methyl-1H-benzo[d]imidazole-4-carboxylate
##STR00211##
[0494] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complex with dichloromethane (2.74 g, 3.36 mmol) was added to a
solution of ethyl
6-bromo-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-car-
boxylate (10 g, 22.4 mmol), bis(neopentyl glycolato)diboron (7.6 g,
33.6 mmol) and potassium acetate (5.5 g, 56.0 mmol) in dioxane (100
mL). Nitrogen was bubbled for 10 minutes and the reaction mixture
was stirred at refluxing temperature for 24 hours. The reaction
mixture was cooled to ambient temperature and the solid was
filtered. The filtrate was dry loaded onto silica gel and purified
by silica gel column chromatography eluting with 25 to 100% ethyl
acetate in hexane to afford ethyl
1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2--
methyl-1H-benzo[d]imidazole-4-carboxylate. ES/MS m/z=412.2
(ArB(OH).sub.2+H).sup.+.
[0495] The following compounds were prepared using a similar
procedure: [0496] ethyl
1-(5,7-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2--
methyl-1H-benzo[d]imidazole-4-carboxylate [0497] ethyl
1-(5,8-dichloroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2--
methyl-1H-benzo[d]imidazole-4-carboxylate [0498] ethyl
1-(5-chloro-8-fluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-y-
l)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0499] ethyl
1-(5-chloroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-meth-
yl-1H-benzo[d]imidazole-4-carboxylate [0500] ethyl
6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-(8-fluoroquinolin-4-yl)-2-meth-
yl-1H-benzo[d]imidazole-4-carboxylate [0501] ethyl
1-(8-chloroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-meth-
yl-1H-benzo[d]imidazole-4-carboxylate [0502] ethyl
6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-(5-fluoroquinolin-4-yl)-2-meth-
yl-1H-benzo[d]imidazole-4-carboxylate [0503] ethyl
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-y-
l)-2-methyl-1H-benzo[d]imidazole-4-carboxylate [0504] ethyl
1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(5,5-dimethy-
l-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazole-4-carboxylate
[0505] ethyl
6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)q-
uinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate [0506] tert-butyl
4-(4-(6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazol-1-yl)q-
uinolin-2-yl)piperazine-1-carboxylate
J. Preparation of Ethyl
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-
-1H-benzo[d]imidazole-4-carboxylate
##STR00212##
[0508] Tetrakis(triphenylphosphine)palladium(0) (241 mg, 0.21 mmol)
was added to a solution of ethyl
1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2--
methyl-1H-benzo[d]imidazole-4-carboxylate (1.0 g, 2.09 mmol),
4-bromo-2-(difluoromethyl)pyridine (521 mg, 2.5 mmol), and
potassium phosphate tribasic (1.11 g, 5.22 mmol) in dioxane (10 mL)
and water (3 mL). Nitrogen was bubbled for 10 minutes and the
reaction mixture was stirred at 90.degree. C. for 4 hours. Upon
cooling, the reaction mixture was partitioned between ethyl acetate
and water. The organic phase was washed with brine, dried with
magnesium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography eluting with 5 to 100% of (20% methanol in ethyl
acetate) in hexane to afford ethyl
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-
-1H-benzo[d]imidazole-4-carboxylate. ES/MS m/z=495.2
(M+H).sup.+.
[0509] The following compounds were prepared using a similar
procedure: [0510] ethyl
6-(2-cyanopyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d-
]imidazole-4-carboxylate [0511] ethyl
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[-
d]imidazole-4-carboxylate [0512] ethyl
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate [0513] ethyl
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-6-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate [0514] ethyl
6-(3-chloro-2-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate [0515] ethyl
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2,3,5-trifluoropyridin-4-yl)-1H-
-benzo[d]imidazole-4-carboxylate [0516] ethyl
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate [0517] ethyl
1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylate [0518] ethyl
1-(5-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxylate [0519] ethyl
6-(2-cyanopyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d-
]imidazole-4-carboxylate [0520] ethyl
6-(2-cyanopyridin-4-yl)-1-(5,8-dichloroquinolin-4-yl)-2-methyl-1H-benzo[d-
]imidazole-4-carboxylate [0521] ethyl
1-(8-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxylate [0522] ethyl
6-(2-cyanopyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxylate [0523] ethyl
6-(2-cyanopyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxylate [0524] ethyl
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylate [0525] ethyl
6-(2-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo-
[d]imidazole-4-carboxylate [0526] ethyl
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyrimidin-4-yl)-1H-benz-
o[d]imidazole-4-carboxylate [0527] ethyl
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(6-methylpyrimidin-4-yl)-1H-benz-
o[d]imidazole-4-carboxylate [0528] ethyl
6-(6-amino-5-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylate [0529] ethyl
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoropyridin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylate [0530] ethyl
6-(2-chloropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylate [0531] ethyl
6-(2,3-difluoropyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylate [0532] ethyl
1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(2,3-difluor-
opyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate [0533] ethyl
1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(2-cyanopyri-
din-4-yl)-1H-benzo[d]imidazole-4-carboxylate [0534] ethyl
6-(2-cyanopyridin-4-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H--
benzo[d]imidazole-4-carboxylate [0535] tert-butyl
4-(4-(6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl-
)piperazine-1-carboxylate
K. Preparation of
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-
-1H-benzo[d]imidazole-4-carboxylic Acid
##STR00213##
[0537] Aqueous 1M lithium hydroxide (3.4 mL) was added to ethyl
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-
-1H-benzo[d]imidazole-4-carboxylate (847 mg, 1.71 mmol) in THF (10
mL). The reaction was stirred at ambient temperature for overnight.
The reaction mixture was acidified with 4N HCl in dioxane. The
resulting solution was concentrated under reduced pressure to
afford
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-
-1H-benzo[d]imidazole-4-carboxylic acid which was used without
further purification for the next step. ES/MS m/z 467.20
(M+H).sup.+.
[0538] The following compounds were prepared using a similar
procedure: [0539]
6-(2-cyanopyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H--
benzo[d]imidazole-4-carboxylic acid [0540]
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[-
d]imidazole-4-carboxylic acid [0541]
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid [0542]
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-6-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid [0543]
6-(3-chloro-2-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid [0544]
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2,3,5-trifluoropyridin-4-yl)-1H-
-benzo[d]imidazole-4-carboxylic acid [0545]
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid [0546]
1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylic acid [0547]
1-(5-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxylic acid [0548]
6-(2-cyanopyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d-
]imidazole-4-carboxylic acid [0549]
6-(2-cyanopyridin-4-yl)-1-(5,8-dichloroquinolin-4-yl)-2-methyl-1H-benzo[d-
]imidazole-4-carboxylic acid [0550]
1-(8-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxylic acid [0551]
6-(2-cyanopyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxylic acid [0552]
6-(2-cyanopyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxylic acid [0553]
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylic acid [0554]
6-(2-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo-
[d]imidazole-4-carboxylic acid [0555]
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyrimidin-4-yl)-1H-benz-
o[d]imidazole-4-carboxylic acid [0556]
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(6-methylpyrimidin-4-yl)-1H-benz-
o[d]imidazole-4-carboxylic acid [0557]
6-(6-amino-5-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxylic acid [0558]
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoropyridin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylic acid [0559]
6-(2-chloropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxylic acid [0560]
6-(2,3-difluoropyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxylic acid [0561]
1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(2,3-difluor-
opyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid [0562]
1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(2-cyanopyri-
din-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid [0563]
6-(2-cyanopyridin-4-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H--
benzo[d]imidazole-4-carboxylic acid
Preparation of the Compounds of Formula (5) According to Reaction
Scheme 1
A. Preparation of
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-
-1H-benzo[d]imidazole-4-carboxamide
##STR00214##
[0565] To a solution of
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-
-1H-benzo[d]imidazole-4-carboxylic acid (797 mg, 1.71 mmol) in DMF
(8.0 mL) were added ammonium chloride (640, 12.0 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (1.31 g, 6.84 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (1.31 g, 6.84 mmol) and diethylisopropylamine (2.98
mL, 17.1 mmol). The mixture was stirred at 50.degree. C. for
overnight. The material was precipitated with the addition of
water. The resulting solid was filtered, washed with water, and
dried under high vacuum for overnight to afford
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-
-1H-benzo[d]imidazole-4-carboxamide. ES/MS m/z 466.2
(M+H).sup.+.
[0566] The following compounds were prepared using a similar
procedure: [0567]
1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d-
]imidazole-4-carboxamide [0568]
6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxamide [0569]
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxamide [0570]
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[-
d]imidazole-4-carboxamide [0571]
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxamide [0572] tert-butyl
(4-(4-carbamoyl-2-ethyl-1-(7-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-y-
l)pyridin-2-yl)carbamate [0573] tert-butyl
(4-(4-carbamoyl-1-(7-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6--
yl)pyridin-2-yl)carbamate [0574] tert-butyl
(4-(4-carbamoyl-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-y-
l)pyridin-2-yl)carbamate [0575] tert-butyl
(4-(4-carbamoyl-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6--
yl)pyridin-2-yl)carbamate [0576] tert-butyl
(4-(4-carbamoyl-2-cyclopropyl-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidaz-
ol-6-yl)pyridin-2-yl)carbamate [0577] tert-butyl
(4-(4-carbamoyl-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6--
yl)pyridin-2-yl)carbamate [0578] tert-butyl
(4-(4-carbamoyl-1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-1H-benzo-
[d]imidazol-6-yl)pyridin-2-yl)carbamate [0579] tert-butyl
(4-(4-carbamoyl-1-(8-chloro-5-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]im-
idazol-6-yl)pyridin-2-yl)carbamate [0580] tert-butyl
(4-(4-carbamoyl-1-(8-chloro-5-fluoroquinolin-4-yl)-2-isopropyl-1H-benzo[d-
]imidazol-6-yl)pyridin-2-yl)carbamate [0581] tert-butyl
(4-(4-carbamoyl-1-(8-chloro-5-fluoroquinolin-4-yl)-2-(oxetan-3-yl)-1H-ben-
zo[d]imidazol-6-yl)pyridin-2-yl)carbamate [0582] tert-butyl
(4-(4-carbamoyl-2-cyclopropyl-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]im-
idazol-6-yl)pyridin-2-yl)carbamate [0583] tert-butyl
(4-(4-carbamoyl-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazol-
-6-yl)pyridin-2-yl)carbamate [0584]
1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-
-yl)-1H-benzo[d]imidazole-4-carboxamide [0585] tert-butyl
(4-(4-carbamoyl-2-(cyclopropylmethyl)-1-(5,8-difluoroquinolin-4-yl)-1H-be-
nzo[d]imidazol-6-yl)pyridin-2-yl)carbamate [0586] tert-butyl
(4-(4-carbamoyl-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazo-
l-6-yl)pyridin-2-yl)carbamate [0587] tert-butyl
(4-(4-carbamoyl-1-(8-chloroquinolin-4-yl)-2-(cyclopropylmethyl)-1H-benzo[-
d]imidazol-6-yl)pyridin-2-yl)carbamate [0588] tert-butyl
(4-(4-carbamoyl-1-(8-chloroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidaz-
ol-6-yl)pyridin-2-yl)carbamate [0589]
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-be-
nzo[d]imidazole-4-carboxamide [0590]
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxamide [0591]
6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxamide [0592]
1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-b-
enzo[d]imidazole-4-carboxamide [0593]
1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxamide [0594]
2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)--
1H-benzo[d]imidazole-4-carboxamide [0595]
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxamide [0596]
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-propyl--
1H-benzo[d]imidazole-4-carboxamide [0597]
6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-propyl-1H-benzo[-
d]imidazole-4-carboxamide [0598]
6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxamide [0599]
2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-1H-b-
enzo[d]imidazole-4-carboxamide [0600]
1-(8-chloro-3-methylquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxamide [0601]
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-6-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxamide [0602]
6-(3-chloro-2-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxamide [0603]
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2,3,5-trifluoropyridin-4-yl)-1H-
-benzo[d]imidazole-4-carboxamide [0604]
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxamide [0605]
1-(3-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxamide [0606]
6-(2,3-difluoropyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxamide [0607]
6-(2,3-difluoropyridin-4-yl)-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d-
]imidazole-4-carboxamide [0608]
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-ben-
zo[d]imidazole-4-carboxamide [0609]
2-(cyclopropylmethyl)-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinoli-
n-4-yl)-1H-benzo[d]imidazole-4-carboxamide [0610]
1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl--
1H-benzo[d]imidazole-4-carboxamide [0611]
1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxamide [0612]
1-(5-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxamide [0613]
6-(2-cyanopyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d-
]imidazole-4-carboxamide [0614]
6-(2-cyanopyridin-4-yl)-1-(5,8-dichloroquinolin-4-yl)-2-methyl-1H-benzo[d-
]imidazole-4-carboxamide [0615]
1-(8-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxamide [0616]
6-(2-cyanopyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxamide [0617]
6-(2-cyanopyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxamide [0618]
1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxamide [0619]
6-(2-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo-
[d]imidazole-4-carboxamide [0620]
1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyrimidin-4-yl)-1H-benz-
o[d]imidazole-4-carboxamide1-(5,8-difluoroq [0621]
uinolin-4-yl)-2-methyl-6-(6-methylpyrimidin-4-yl)-1H-benzo[d]imidazole-4--
carboxamide [0622]
1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoropyridin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxamide [0623]
6-(2-chloropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[-
d]imidazole-4-carboxamide [0624]
6-(2,3-difluoropyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxamide [0625] tert-butyl
4-(4-(4-carbamoyl-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)q-
uinolin-2-yl)piperazine-1-carboxylate [0626] tert-butyl
4-(4-(4-carbamoyl-6-(2-cyanopyridin-4-yl)-1H-benzo[d]imidazol-1-yl)quinol-
in-2-yl)piperazine-1-carboxylate [0627]
6-(2-cyanopyridin-4-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H--
benzo[d]imidazole-4-carboxamide
[0628] Compounds may be referred to by Example number with
reference to the below tables.
TABLE-US-00006 Example Name MS NMR 5 1-(8-chloroquinolin- 400.0 1H
NMR (400 MHz, DMSO-d6) 4-yl)-6-pyridin-4- .delta. 9.30 (dd, J =
4.5, 0.6 Hz, 1H), ylbenzimidazole-4- 9.08 (d, J = 3.0 Hz, 1H), 9.06
(d, J = 0.6 Hz, carboxamide 1H), 8.76-8.70 (m, 2H), 8.47 (dd, J =
1.8, 0.6 Hz, 1H), 8.14-8.05 (m, 6H), 7.65-7.58 (m, 1H), 7.57-7.52
(m, 1H). 6 1-(5,8- 416.1 1H NMR (400 MHz, DMSO-d6)
difluoroquinolin-4- .delta. 9.32 (d, J = 4.5 Hz, 1H),
yl)-2-methyl-6- 9.10 (d, J = 3.0 Hz, 1H), pyridin-4- 8.74-8.67 (m,
2H), 8.41 (dd, J = 1.8, 0.6 Hz, ylbenzimidazole-4- 1H), 8.12-8.03
(m, 4H), carboxamide 7.94 (dd, J = 1.9, 0.6 Hz, 1H), 7.78 (td, J =
9.6, 4.2 Hz, 1H), 7.45 (ddd, J = 12.2, 8.7, 3.7 Hz, 1H), 2.46 (s,
3H). 7 1-(8-chloro-2- 428.1 1H NMR (400 MHz, DMSO-d6)
methylquinolin-4-yl)- .delta. 9.13 (d, J = 3.1 Hz, 1H),
2-methyl-6-pyridin- 8.68 (d, J = 5.9 Hz, 2H), 8.41 (d, J = 1.8 Hz,
4-ylbenzimidazole-4- 1H), 8.07 (s, 1H), carboxamide 8.10-7.98 (m,
3H), 7.93 (s, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.52-7.42 (m, 1H),
7.24-7.18 (m, 1H), 2.83 (s, 3H), 2.46 (d, J = 0.6 Hz, 3H). 8
1-(5-fluoroquinolin- 398.1 1H NMR (400 MHz, DMSO-d6)
4-yl)-2-methyl-6- .delta. 9.27 (d, J = 4.5 Hz, 1H), 9.12 (s,
pyridin-4- 1H), 8.76-8.71 (m, 2H), 8.42 (d, ylbenzimidazole-4- J =
1.8 Hz, 1H), 8.16 (dd, J = 7.5, carboxamide 5.6 Hz, 3H), 8.08 (s,
1H), 7.97-7.93 (m, 2H), 7.45 (dd, J = 12.4, 7.8 Hz, 1H), 2.44 (d, J
= 0.8 Hz, 3H). 9 2-methyl-1-(5- 394.1 1H NMR (400 MHz, DMSO-d6)
methylquinolin-4-yl)- .delta. 9.16 (dd, J = 4.4, 0.6 Hz, 1H),
6-pyridin-4- 9.12 (d, J = 3.0 Hz, 1H), ylbenzimidazole-4- 8.76-8.71
(m, 2H), 8.45 (dd, J = 1.9, carboxamide 0.7 Hz, 1H), 8.23-8.18 (m,
2H), 8.15 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 3.0 Hz, 1H), 7.86 (dd,
J = 1.9, 0.7 Hz, 1H), 7.82-7.76 (m, 2H), 7.47 (d, J = 7.0 Hz, 1H),
2.39 (s, 3H), 1.72 (s, 3H). 10 2-methyl-1-(2- 394.2 1H NMR (400
MHz, DMSO-d6) methylquinolin-4-yl)- .delta. 9.15 (s, 1H), 8.70 (d,
J = 5.7 Hz, 6-pyridin-4- 2H), 8.42 (d, J = 1.8 Hz, 1H),
ylbenzimidazole-4- 8.16 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.1 Hz,
carboxamide 3H), 7.89-7.76 (m, 3H), 7.59-7.45 (m, 1H), 7.25 (d, J =
8.4 Hz, 1H), 2.80 (s, 3H), 2.45 (s, 3H). 11 1-(8-chloro-5- 432.1 1H
NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)- .delta. 9.39 (d, J =
4.5 Hz, 1H), 2-methyl-6-pyridin- 9.10 (d, J = 3.1 Hz, 1H),
4-ylbenzimidazole-4- 8.75-8.68 (m, 2H), 8.42 (d, J = 1.8 Hz, 1H),
carboxamide 8.15-8.04 (m, 5H), 7.96 (d, J = 1.8 Hz, 1H), 7.46 (dd,
J = 11.9, 8.5 Hz, 1H), 2.46 (s, 3H). 12 1-(8-chloroquinolin- 456.2
1H NMR (400 MHz, DMSO-d6) 4-yl)-2-(oxetan-3-yl)- .delta. 9.31 (d, J
= 4.4 Hz, 1H), 6-pyridin-4- 9.19 (d, J = 3.0 Hz, 1H),
ylbenzimidazole-4- 8.79-8.72 (m, 3H), 8.50 (d, J = 1.8 Hz, 1H),
carboxamide 8.23-8.15 (m, 4H), 8.09 (dd, J = 7.6, 1.2 Hz, 1H),
7.97-7.91 (m, 2H), 7.57-7.51 (m, 1H), 7.26 (dd, J = 8.5, 1.2 Hz,
1H), 5.04 (t, J = 6.2 Hz, 1H), 4.95 (t, J = 6.1 Hz, 1H), 4.72 (dd,
J = 8.6, 5.6 Hz, 1H), 4.55 (dd, J = 8.5, 5.6 Hz, 1H), 4.32-4.21 (m,
1H). 13 1-(8-chloroquinolin- 414.1 1H NMR (400 MHz, DMSO-d6)
4-yl)-2-methyl-6- .delta. 9.32 (d, J = 4.5 Hz, 1H), pyridin-4- 9.14
(d, J = 3.2 Hz, 1H), ylbenzimidazole-4- 8.55-8.50 (m, 2H), 8.31 (d,
J = 1.8 Hz, 1H), carboxamide 8.09 (dd, J = 7.5, 1.2 Hz, 1H), 8.02
(dd, J = 8.3, 3.9 Hz, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.65-7.61 (m,
2H), 7.57 (dd, J = 8.5, 7.5 Hz, 1H), 7.29 (dd, J = 8.5, 1.2 Hz,
1H), 2.44 (s, 3H). 14 1-(8-chloroquinolin- 432.1 1H NMR (400 MHz,
DMSO-d6) 4-yl)-6-(3- .delta. 9.31 (dd, J = 4.5, 0.6 Hz, 1H),
fluoropyridin-4-yl)-2- 9.12 (s, 1H), 8.58 (d, J = 2.7 Hz,
methylbenzimidazole- 1H), 8.39 (dd, J = 5.1, 0.9 Hz, 4-carboxamide
1H), 8.22 (t, J = 1.7 Hz, 1H), 8.09 (dd, J = 7.6, 1.3 Hz, 1H), 8.04
(d, J = 4.5 Hz, 2H), 7.63-7.50 (m, 3H), 7.33 (dd, J = 8.4, 1.2 Hz,
1H), 2.47 (s, 3H). 15 1-(8-chloroquinolin- 428.1 1H NMR (400 MHz,
DMSO-d6) 4-yl)-2-methyl-6-(2- .delta. 9.35 (dd, J = 4.5, 0.7 Hz,
1H), methylpyridin-4- 9.14 (d, J = 3.2 Hz, 1H), 8.62 (d, J = 6.2
Hz, yl)benzimidazole-4- 1H), 8.46 (s, 1H), carboxamide 8.13-8.08
(m, 3H), 8.05 (d, J = 4.5 Hz, 1H), 7.85 (s, 1H), 7.62-7.54 (m, 1H),
7.35-7.27 (m, 1H), 2.62 (s, 3H), 2.45 (d, J = 0.8 Hz, 3H). 16
6-(2-cyanopyridin-4- 441.1 1H NMR (400 MHz, DMSO-d6) yl)-1-(5,8-
.delta. 9.32 (d, J = 4.5 Hz, 1H), difluoroquinolin-4- 9.10 (d, J =
3.1 Hz, 1H), 8.69 (dd, J = 5.3, yl)-2- 0.8 Hz, 1H), 8.38-8.33 (m,
methylbenzimidazole- 2H), 8.09-8.01 (m, 3H), 7.90 (d, 4-carboxamide
J = 1.8 Hz, 1H), 7.82-7.74 (m, 1H), 7.46 (ddd, J = 12.4, 8.7, 3.8
Hz, 1H), 2.44 (s, 3H). 157 6-(6-amino-5- 457.1 1H NMR (400 MHz,
DMSO-d6) cyanopyrimidin-4- .delta. 9.30 (d, J = 4.5 Hz, 1H),
yl)-1-(5,8- 9.08 (d, J = 3.1 Hz, 1H), difluoroquinolin-4- 8.52-8.43
(m, 2H), 8.05 (dd, J = 23.3, 3.8 Hz, yl)-2-methyl-1H- 2H),
7.83-7.70 (m, 2H), benzo[d]imidazole-4- 7.45 (ddd, J = 12.3, 8.8,
3.8 Hz, carboxamide 1H), 2.49 (s, 3H).
B. Preparation of
6-(2-aminopyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxamide
##STR00215##
[0630] tert-Butyl
(4-(4-carbamoyl-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6--
yl)pyridin-2-yl)carbamate (50 mg, 0.10 mmol) was dissolved in
dichloromethane (1.0 mL) and trifluoroacetic acid (145 .mu.L, 1.89
mmol) was added. The reaction mixture was stirred at ambient
temperature for 1 hour, after which the reaction was concentrated
under reduced pressure. The resultant was purified by HPLC eluting
with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). The
appropriate fractions were pooled and lyophilized to afford
6-(2-aminopyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imi-
dazole-4-carboxamide as a 2,2,2-trifluoroacetic acid salt (Example
23).
TABLE-US-00007 Example Name MS NMR 17 6-(2-aminopyridin-4- 431.1 1H
NMR (400 MHz, DMSO-d6) yl)-1-(5,8- .delta. 9.31 (d, J = 4.5 Hz,
1H), 9.09 (s, difluoroquinolin-4- 1H), 8.30 (d, J = 1.8 Hz, 1H),
yl)-2- 8.06 (d, J = 4.2 Hz, 3H), 7.88 (d, J = 6.8 Hz,
methylbenzimidazole- 1H), 7.86-7.73 (m, 4-carboxamide 3H),
7.52-7.37 (m, 1H), 7.22 (d, J = 1.4 Hz, 1H), 7.20-7.17 (m, 1H),
2.44 (d, J = 1.0 Hz, 3H), 18 6-(2-aminopyridin-4- 447.1 1H NMR (400
MHz, DMSO-d6) yl)-1-(8-chloro-5- .delta. 9.38 (d, J = 4.5 Hz, 1H),
9.09 (s, fluoroquinolin-4-yl)- 1H), 8.30 (d, J = 1.9 Hz, 1H), 2-
8.12 (dd, J = 8.6, 4.9 Hz, 1H), methylbenzimidazole- 8.08 (d, J =
4.5 Hz, 2H), 7.87 (d, J = 6.9 Hz, 4-carboxamide 2H), 7.81 (d, J =
1.9 Hz, 1H), 7.47 (dd, J = 11.9, 8.6 Hz, 1H), 7.24 (s, 1H), 7.19
(d, J = 6.9 Hz, 1H), 2.44 (s, 3H). 19 6-(2-aminopyrimidin- 430.1 1H
NMR (400 MHz, DMSO-d6) 4-yl)-1-(8- .delta. 9.34 (d, J = 4.5 Hz,
1H), chloroquinolin-4-yl)- 9.13 (d, J = 3.1 Hz, 1H), 8.77 (d, J =
1.7 Hz, 2- 1H), 8.22 (d, J = 5.7 Hz, methylbenzimidazole- 1H),
8.14-8.08 (m, 1H), 8.06 (d, 4-carboxamide J = 4.5 Hz, 1H), 8.01 (d,
J = 3.1 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.58 (dd, J = 8.4, 7.6
Hz, 1H), 7.30 (dd, J = 8.5, 1.2 Hz, 1H), 7.24 (d, J = 5.8 Hz, 1H),
2.44 (s, 3H). 20 1-(8-chloroquinolin- 455.1 1H NMR (400 MHz,
DMSO-d6) 4-yl)-2-methyl-6- .delta. 9.61 (s, 1H), 9.37 (d, J = 4.5
Hz, (9H-purin-6- 1H), 9.17 (d, J = 3.1 Hz, 1H), yl)benzimidazole-4-
8.82 (s, 1H), 8.55 (s, 1H), 8.52 (s, carboxamide 1H), 8.15-8.08 (m,
2H), 7.99 (d, J = 3.1 Hz, 1H), 7.59 (dd, J = 8.5, 7.6 Hz, 1H), 7.37
(dd, J = 8.5, 1.2 Hz, 1H), 2.47 (s, 3H). 21 6-(6-aminopyrimidin-
430.1 1H NMR (400 MHz, DMSO-d6) 4-yl)-1-(8- .delta. 9.35 (d, J =
4.5 Hz, 1H), chloroquinolin-4-yl)- 9.12 (d, J = 3.1 Hz, 1H), 8.54
(s, 1H), 2- 8.46 (d, J = 1.8 Hz, 1H), 8.26 (s, methylbenzimidazole-
3H), 8.15-8.05 (m, 3H), 7.71 (d, 4-carboxamide J = 1.8 Hz, 1H),
7.59 (dd, J = 8.5, 7.6 Hz, 1H), 7.31 (dd, J = 8.5, 1.2 Hz, 1H),
6.93 (d, J = 0.8 Hz, 1H), 2.47-2.45 (m, 3H). 22
1-(8-chloroquinolin- 445.1 1H NMR (400 MHz, DMSO-d6) 4-yl)-6-(2,6-
.delta. 11.85 (s, 1H), 9.34 (d, J = 4.5 Hz, diaminopyrimidin-4-
1H), 9.13 (d, J = 3.1 Hz, 1H), yl)-2- 8.30 (s, 1H), 8.17-7.97 (m,
5H), methylbenzimidazole- 7.63-7.59 (m, 1H), 7.58 (d, J = 1.7 Hz,
4-carboxamide 1H), 7.30 (dd, J = 8.5, 1.2 Hz, 1H), 6.26 (s, 1H),
2.45 (s, 3H). 23 6-(2-aminopyridin-4- 429.1 1H NMR (400 MHz,
DMSO-d6) yl)-1-(8- .delta. 9.33 (d, J = 4.5 Hz, 1H),
chloroquinolin-4-yl)- 9.12 (d, J = 3.1 Hz, 1H), 8.32 (d, J = 1.8
Hz, 2- 1H), 8.09 (td, J = 7.6, 2.2 Hz, methylbenzimidazole- 2H),
8.04 (d, J = 4.5 Hz, 1H), 4-carboxamide 7.87 (d, J = 6.8 Hz, 1H),
7.83 (s, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 8.4, 7.6 Hz,
1H), 7.28 (dd, J = 8.5, 1.2 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.16
(dd, J = 6.8, 1.9 Hz, 1H), 2.45 (s, 3H).
C. Preparation of
6-(2-amino-3-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1-
H-benzo[d]imidazole-4-carboxamide
##STR00216##
[0632] Ammonium hydroxide (28-30% solution in water, 0.75 mL) was
added to a solution of
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-be-
nzo[d]imidazole-4-carboxamide (40 mg, 0.09 mmol) in DMSO (2.0 mL).
The sealed tube was closed and reaction mixture was stirred at
100.degree. C. for overnight. The excess ammonia was removed under
reduced pressure and the resulting solution was purified by HPLC
eluting with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic
acid). The appropriate fractions were pooled and lyophilized to
afford
6-(2-amino-3-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1-
H-benzo[d]imidazole-4-carboxamide as a 2,2,2-trifluoroacetic acid
salt (Example 26).
[0633] The following compounds were prepared using a similar
procedure:
TABLE-US-00008 Example Name MS NMR 24 6-(2-aminopyridin-4- 477.2 1H
NMR (400 MHz, DMSO-d6) yl)-1-(5,8- .delta. 9.29 (d, J = 4.5 Hz,
1H), difluoroquinolin-4- 9.16 (d, J = 3.3 Hz, 1H), 8.17 (t, J = 1.6
Hz, yl)-2- 1H), 8.08 (d, J = 4.5 Hz, methylbenzimidazole- 1H), 8.02
(d, J = 3.2 Hz, 1H), 4-carboxamide 7.77 (td, J = 9.5, 4.2 Hz, 1H),
7.71 (d, J = 6.0 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.45 (ddd, J =
12.3, 8.8, 3.8 Hz, 1H), 6.78 (t, J = 5.7 Hz, 1H), 2.68 (td, J =
7.4, 1.7 Hz, 2H), 1.72 (h, J = 7.4 Hz, 2H), 0.87 (t, J = 7.4 Hz,
3H). 25 6-(2-aminopyridin-4- 491.2 1H NMR (400 MHz, DMSO-d6)
yl)-1-(8-chloro-5- .delta. 9.37 (d, J = 4.5 Hz, 1H),
fluoroquinolin-4-yl)- 8.97 (d, J = 3.3 Hz, 1H), 2- 8.18-8.08 (m,
3H), 7.94 (d, J = 3.3 Hz, 1H), methylbenzimidazole- 7.73-7.68 (m,
1H), 7.57 (s, 1H), 4-carboxamide 7.49 (dd, J = 11.8, 8.6 Hz, 1H),
6.78 (t, J = 5.9 Hz, 1H), 1.80-1.72 (m, 1H), 1.30-1.23 (d, J = 5.6
Hz, 1H), 1.20-1.11 (m, 1H), 1.07-0.93 (m, 2H). 26
6-(2-aminopyrimidin- 449.1 1H NMR (400 MHz, DMSO-d6) 4-yl)-1-(8-
.delta. 9.29 (d, J = 4.5 Hz, 1H), chloroquinolin-4-yl)- 9.10 (d, J
= 3.2 Hz, 1H), 8.17 (t, J = 1.7 Hz, 2- 1H), 8.07 (d, J = 4.5 Hz,
methylbenzimidazole- 1H), 8.02 (d, J = 3.2 Hz, 1H), 4-carboxamide
7.82-7.74 (m, 1H), 7.71 (d, J = 6.0 Hz, 1H), 7.57 (t, J = 1.3 Hz,
1H), 7.46 (ddd, J = 12.4, 8.8, 3.9 Hz, 1H), 6.80 (t, J = 5.8 Hz,
1H), 2.45 (s, 3H).
Preparation of the Compounds of Formula (5) According to Reaction
Scheme 3
A. Preparation of Ethyl
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate
##STR00217##
[0635] A solution ethyl
2-amino-5-bromo-3-((5,8-difluoroquinolin-4-yl)amino)benzoate (3.7
g, 8.76 mmol, made as described above) in trimethyl orthoformate
(50 mL) was refluxed for 30 minutes. Upon cooling, the mixture was
concentrated under reduced pressure. The resulting solid was
triturated with 25 mL of diethyl ether. The solid was recovered by
filtration to afford ethyl
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate.
ES/MS m/z=432.0 (M+H.sup.+).
B. Preparation of
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic
Acid
##STR00218##
[0637] Aqueous 1M lithium hydroxide (3.4 mL) was added to ethyl
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate
(1.19 g, 2.75 mmol) in THF (15 mL). The reaction was stirred at
ambient temperature for 1 hour. The reaction mixture was acidified
with 4N HCl in dioxane. The resulting solution was concentrated
under reduced pressure to afford
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-ca-
rboxylic acid which was used without further purification for the
next step. ES/MS m/z 404.0 (M+H).sup.+.
C. Preparation of
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide
##STR00219##
[0639] To a solution of
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic
acid (1.11 g, 2.75 mmol) in DMF (9.0 mL) were added ammonium
chloride (1.03 g, 19.2 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (2.10
g, 11.0 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (2.10 g, 11.0 mmol) and diethylisopropylamine (4.8
mL, 27.5 mmol). The mixture was stirred at 50.degree. C. for
overnight. The material was precipitated with the addition of
water. The resulting solid was filtered, washed with water, and
dried under high vacuum to afford
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide
ES/MS m/z 403.0 (M+H).sup.+.
D. Preparation of
1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-
-benzo[d]imidazole-4-carboxamide
##STR00220##
[0641] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complex with dichloromethane (276 mg, 0.34 mmol) was added to a
solution of
6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide
(910 mg, 2.26 mmol), bis(neopentyl glycolato)diboron (663 mg, 2.93
mmol) and potassium acetate (554 mg, 5.64 mmol) in dioxane (20 mL).
Nitrogen was bubbled for 10 minutes and the reaction mixture was
stirred at refluxing temperature for 24 hours. The reaction mixture
was cooled to ambient temperature and the solid was filtered. The
solid was washed with water and dried under vacuum to afford
1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-
-benzo[d]imidazole-4-carboxamide ES/MS m/z=369.2
(ArB(OH).sub.2+H).sup.+.
E. Preparation of
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imi-
dazole-4-carboxamide
##STR00221##
[0643] Tetrakis(triphenylphosphine)palladium(0) (146 mg, 0.13 mmol)
was added to a solution of
1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-
-benzo[d]imidazole-4-carboxamide (550 mg, 1.26 mmol),
4-iodo-2,3-difluoropyridine (365 mg, 1.51 mmol), and potassium
phosphate tribasic (669 mg, 3.15 mmol) in dioxane (6.0 mL) and
water (1.5 mL). Nitrogen was bubbled for 10 minutes and the
reaction mixture was stirred at 100.degree. C. for 4 hours. Upon
cooling, the reaction mixture was partitioned between ethyl acetate
and water. The organic phase was washed with brine, dried with
magnesium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography eluting with 5 to 100% of (10% methanol in ethyl
acetate) in hexane to afford
6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imi-
dazole-4-carboxamide. ES/MS m/z=438.2 (M+H).sup.+.
Preparation of Compounds of Formula (IM)
A. Preparation of
4-(6-(2-(difluoromethyl)pyridin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)--
1H-benzo[d]imidazol-1-yl)-5,8-difluoroquinoline
##STR00222##
[0645]
6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2--
methyl-1H-benzo[d]imidazole-4-carboxamide (455 mg, 0.98 mmol) was
suspended in 1,1-dimethoxy-N,N-dimethylmethanamine (6.5 mL, 49
mmol) and stirred at 100.degree. C. for 5 hours. The solution was
cooled to ambient temperature, concentrated under reduced pressure
and dried under vacuum overnight. The residue was dissolved in
acetic acid (5 mL) and hydrazine (92 .mu.L, 2.93 mmol) was added.
The reaction mixture was stirred at 45.degree. C. for 1 hour, after
which the reaction was cooled to ambient temperature and
concentrated under reduced pressure. The resultant was purified by
HPLC eluting with 5-95% water/acetonitrile (0.1% v/v
trifluoroacetic acid). The appropriate fractions were pooled and
lyophilized to afford
4-(6-(2-(difluoromethyl)pyridin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)--
1H-benzo[d]imidazol-1-yl)-5,8-difluoroquinoline as a
2,2,2-trifluoroacetic acid salt (Example 43).
[0646] The following compounds were prepared using a similar
procedure: [0647] tert-butyl
4-(4-(6-(2-cyanopyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidaz-
ol-1-yl)quinolin-2-yl)piperazine-1-carboxylate [0648]
4-(4-(4H-1,2,4-triazol-3-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl-
)-1H-benzo[d]imidazol-6-yl)picolinonitrile
TABLE-US-00009 [0648] Example Name MS NMR 27
8-chloro-4-[6-pyridin-4- 424.0 1H NMR (400 MHz, DMSO-d6)
yl-4-(1H-1,2,4-triazol-5- .delta. 9.34-9.26 (m, 1H), 9.02 (s,
yl)benzimidazol-1- 1H), 8.77-8.71 (m, 2H), yl]quinoline 8.48 (d, J
= 1.7 Hz, 1H), 8.39 (s, 1H), 8.14-8.06 (m, 4H), 7.99 (d, J = 1.7
Hz, 1H), 7.63 (dd, J = 8.5, 7.4 Hz, 1H), 7.55 (dd, J = 8.5, 1.3 Hz,
1H). 28 5,8-difluoro-4-[2- 440.1 1H NMR (400 MHz, DMSO-d6)
methyl-6-pyridin-4-yl- .delta. 9.33 (d, J = 4.5 Hz, 1H),
4-(4H-1,2,4-triazol-3- 8.78-8.73 (m, 2H), 8.46 (dd, J = 1.8,
yl)benzimidazol-1- 0.6 Hz, 1H), 8.23-8.16 (m, 2H), yl]quinoline
8.09 (d, J = 4.5 Hz, 1H), 7.91 (dd, J = 1.8, 0.6 Hz, 1H), 7.79 (td,
J = 9.5, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3, 8.7, 3.8 Hz, 1H), 2.50
(s, 3H). 29 5,8-dichloro-4-[2- 472.1 1H NMR (400 MHz, DMSO-d6)
methyl-6-pyridin-4-yl- .delta. 9.40 (dd, J = 4.4, 0.6 Hz, 1H),
4-(4H-1,2,4-triazol-3- 8.76-8.71 (m, 2H), 8.46 (d, J = 1.7 Hz,
yl)benzimidazol-1- 1H), 8.17 (d, J = 5.9 Hz, yl]quinoline 2H), 8.12
(dd, J = 8.3, 0.6 Hz, 1H), 8.09 (dd, J = 4.4, 0.7 Hz, 1H), 7.86 (d,
J = 1.7 Hz, 1H), 7.77 (dd, J = 8.3, 0.6 Hz, 1H), 2.45 (s, 3H). 30
5-fluoro-4-[2-methyl-6- 422.1 1H NMR (400 MHz, DMSO-d6)
pyridin-4-yl-4-(4H- .delta. 9.32-9.25 (m, 1H), 8.80 (dt, J = 5.6,
1,2,4-triazol-3- 0.8 Hz, 2H), 8.52 (s, 1H), yl)benzimidazol-1- 8.50
(dd, J = 1.8, 0.7 Hz, 1H), yl]quinoline 8.31-8.27 (m, 2H), 8.17
(dd, J = 8.5, 0.9 Hz, 1H), 7.99 (dd, J = 4.5, 0.7 Hz, 1H),
7.95-7.93 (m, 1H), 7.93-7.88 (m, 1H), 7.47 (ddd, J = 12.4, 7.9, 0.9
Hz, 1H), 2.51 (s, 3H). 31 5-methyl-4-[2-methyl-6- 418.1 1H NMR (400
MHz, DMSO-d6) pyridin-4-yl-4-(4H- .delta. 9.18 (d, J = 4.4 Hz, 1H),
1,2,4-triazol-3- 8.79-8.75 (m, 2H), 8.50 (dd, J = 1.7,
yl)benzimidazol-1- 0.6 Hz, 1H), 8.28-8.25 (m, 2H), yl]quinoline
8.18-8.14 (m, 1H), 7.84-7.76 (m, 4H), 7.48 (d, J = 7.0 Hz, 1H),
2.43 (s, 3H), 1.76 (s, 3H). 32 8-chloro-2-methyl-4-[2- 452.1 1H NMR
(400 MHz, DMSO-d6) methyl-6-pyridin-4-yl- .delta. 8.68 (d, J = 5.9
Hz, 2H), 4-(4H-1,2,4-triazol-3- 8.43 (s, 1H), 8.03 (d, J = 7.2 Hz,
3H), yl)benzimidazol-1- 7.95 (s, 1H), 7.75 (s, 1H), yl]quinoline
7.49 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H), 2.84 (s, 3H). 33
5,8-difluoro-4-[2- 454.2 1H NMR (400 MHz, DMSO-d6)
methyl-4-(5-methyl-4H- .delta. 9.33 (d, J = 4.5 Hz, 1H),
1,2,4-triazol-3-yl)-6- 8.76-8.73 (m, 2H), 8.42 (d, J = 1.8 Hz,
pyridin-4- 1H), 8.21-8.16 (m, 2H), ylbenzimidazol-1- 8.09 (d, J =
4.5 Hz, 1H), 7.89 (d, J = 1.8 Hz, yl]quinoline 1H), 7.79 (ddd, J =
10.1, 8.8, 4.3 Hz, 1H), 7.47 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 2.50
(s, 3H), 2.47 (s, 3H). 34 2-methyl-4-[2-methyl-6- 418.2 1H NMR (400
MHz, DMSO-d6) pyridin-4-yl-4-(4H- .delta. 8.84-8.77 (m, 3H), 8.58
(s, 1,2,4-triazol-3- 1H), 8.53 (d, J = 1.7 Hz, 1H),
yl)benzimidazol-1- 8.28-8.24 (m, 2H), 8.19 (dt, J = 8.5,
yl]quinoline 1.0 Hz, 1H), 7.94-7.82 (m, 3H), 7.56 (ddd, J = 8.2,
7.0, 1.2 Hz, 1H), 7.40-7.35 (m, 1H), 2.82 (s, 3H), 2.54 (s, 3H). 35
8-chloro-4-[2-methyl-4- 452.2 1H NMR (400 MHz, DMSO-d6)
(5-methyl-4H-1,2,4- .delta. 9.34 (dd, J = 8.2, 4.5 Hz, 1H),
triazol-3-yl)-6-pyridin- 8.70 (ddd, J = 4.9, 3.5, 1.9 Hz,
4-ylbenzimidazol-1- 5H), 8.43 (d, J = 1.8 Hz, 1H), yl]quinoline
8.34 (d, J = 1.8 Hz, 1H), 8.13-8.05 (m, 8H), 8.02 (dd, J = 4.6, 1.2
Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H),
7.62-7.58 (m, 1H), 7.58-7.53 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H),
7.28 (dd, J = 8.4, 1.3 Hz, 1H), 4.00 (s, 3H), 2.43 (s, 3H). 36
8-chloro-4-[2-(oxetan-3- 480.2 1H NMR (400 MHz, DMSO-d6)
yl)-6-pyridin-4-yl-4- .delta. 9.34-9.28 (m, 1H),
(4H-1,2,4-triazol-3- 8.77-8.70 (m, 3H), 8.51 (d, J = 1.8 Hz,
yl)benzimidazol-1- 1H), 8.16 (d, J = 5.9 Hz, 3H), yl]quinoline 8.09
(dd, J = 7.5, 1.3 Hz, 1H), 7.96 (d, J = 4.5 Hz, 1H), 7.80 (d, J =
1.7 Hz, 1H), 7.55 (dd, J = 8.5, 7.5 Hz, 1H), 7.24 (dd, J = 8.5, 1.3
Hz, 1H), 5.16 (dt, J = 35.1, 6.2 Hz, 2H), 4.69 (dd, J = 8.6, 5.6
Hz, 1H), 4.51 (dd, J = 8.5, 5.5 Hz, 1H), 4.32-4.22 (m, 1H). 37
8-chloro-5-fluoro-4-[2- 456.1 1H NMR (400 MHz, DMSO-d6)
methyl-6-pyridin-4-yl- .delta. 9.39 (d, J = 4.5 Hz, 1H),
4-(4H-1,2,4-triazol-3- 9.10 (d, J = 3.1 Hz, 1H), yl)benzimidazol-1-
8.75-8.68 (m, 2H), 8.42 (d, J = 1.8 Hz, 1H), yl]quinoline 8.15-8.04
(m, 5H), 7.96 (d, J = 1.8 Hz, 1H), 7.46 (dd, J = 11.9, 8.5 Hz, 1H),
2.46 (s, 3H). 38 8-chloro-4-[2-methyl-6- 438.1 1H NMR (400 MHz,
DMSO-d6) pyridin-4-yl-4-(4H- .delta. 9.34 (d, J = 4.5 Hz, 1H),
1,2,4-triazol-3- 8.71-8.67 (m, 2H), 8.44 (d, J = 1.8 Hz,
yl)benzimidazol-1- 1H), 8.10 (dd, J = 7.5, 1.2 Hz, yl]quinoline
1H), 8.05 (dd, J = 10.9, 5.1 Hz, 3H), 7.74 (d, J = 1.7 Hz, 1H),
7.59 (dd, J = 8.5, 7.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 2.47 (s,
3H). 39 8-chloro-4-[6-(3- 456.1 1H NMR (400 MHz, DMSO-d6)
fluoropyridin-4-yl)-2- .delta. 9.33 (dd, J = 4.5, 0.6 Hz, 1H),
methyl-4-(4H-1,2,4- 8.60 (d, J = 2.6 Hz, 1H), 8.51 (s, triazol-3-
1H), 8.43-8.39 (m, 1H), yl)benzimidazol-1- 8.30 (d, J = 1.9 Hz,
1H), 8.11 (dt, J = 7.4, yl]quinoline 1.0 Hz, 1H), 8.08 (d, J = 4.5
Hz, 1H), 7.63-7.55 (m, 2H), 7.49 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H),
2.54 (s, 3H). 40 8-chloro-4-[2-methyl-6- 425.1 1H NMR (400 MHz,
DMSO-d6) (2-methylpyridin-4-yl)- .delta. 9.36 (dd, J = 4.5, 0.6 Hz,
1H), 4-(4H-1,2,4-triazol-3- 8.67 (d, J = 6.2 Hz, 1H), 8.50 (d,
yl)benzimidazol-1- J = 1.8 Hz, 1H), 8.46 (s, 1H), yl]quinoline 8.20
(s, 1H), 8.14-8.05 (m, 3H), 7.80 (d, J = 1.7 Hz, 1H), 7.59 (ddd, J
= 8.4, 7.5, 0.6 Hz, 1H), 7.33 (dt, J = 8.5, 0.9 Hz, 1H), 2.65 (s,
3H), 2.48 (s, 3H). 41 4-[6-(2,5- 476.2 1H NMR (400 MHz, DMSO-d6)
difluoropyridin-4-yl)-2- .delta. 9.32 (d, J = 4.5 Hz, 1H),
methyl-4-(4H-1,2,4- 8.45 (s, 1H), 8.30-8.29 (m, 1H), triazol-3-
8.28-8.27 (m, 1H), 8.09 (d, J = 4.5 Hz, yl)benzimidazol-1-yl]- 1H),
7.82-7.75 (m, 1H), 5,8-difluoroquinoline 7.64 (s, 1H), 7.51-7.43
(m, 2H), 2.52 (s, 3H). 42 4-[6-(2,3- 476.1 1H NMR (400 MHz,
DMSO-d6) difluoropyridin-4-yl)-2- .delta. 9.31 (d, J = 4.5 Hz, 1H),
methyl-4-(4H-1,2,4- 8.42 (brs, 1H), 8.24 (t, J = 1.6 Hz, triazol-3-
1H), 8.09 (d, J = 4.5 Hz, 1H), yl)benzimidazol-1-yl]- 8.01 (dd, J =
5.3, 1.1 Hz, 1H), 5,8-difluoroquinoline 7.83-7.74 (m, 1H), 7.60 (t,
J = 1.3 Hz, 1H), 7.56 (t, J = 5.1 Hz, 1H), 7.47 (ddd, J = 12.4,
8.8, 3.8 Hz, 1H), 2.51 (s, 3H). 43 4-[6-[2- 490.1 1H NMR (400 MHz,
DMSO-d6) (difluoromethyl)pyridin- .delta. 9.34 (d, J = 4.5 Hz, 1H),
4-yl]-2-methyl-4-(4H- 8.66 (dd, J = 5.2, 0.7 Hz, 1H), 8.53 (s,
1,2,4-triazol-3- 1H), 8.41 (d, J = 1.7 Hz, 1H),
yl)benzimidazol-1-yl]- 8.11 (d, J = 4.5 Hz, 1H),
5,8-difluoroquinoline 7.97 (dd, J = 1.9, 0.7 Hz, 1H), 7.91-7.87 (m,
1H), 7.86 (d, J = 1.7 Hz, 1H), 7.79 (ddd, J = 10.0, 8.8, 4.2 Hz,
1H), 7.48 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 6.96 (t, J = 54.8 Hz,
1H), 2.53 (s, 3H). 44 4-[3-(5,8- 465.1 1H NMR (400 MHz, DMSO-d6)
difluoroquinolin-4-yl)- .delta. 9.34 (d, J = 4.5 Hz, 1H),
2-methyl-7-(4H-1,2,4- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.50 (s,
triazol-3- 1H), 8.43 (d, J = 1.7 Hz, 1H), yl)benzimidazol-5- 8.39
(dd, J = 2.0, 0.8 Hz, 1H), yl]pyridine-2- 8.11-8.07 (m, 2H), 7.87
(d, J = 1.7 Hz, carbonitrile 1H), 7.79 (ddd, J = 10.1, 8.8, 4.3 Hz,
1H), 7.48 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.52 (s, 3H). 45
5,8-difluoro-4-[2- 454.2 1H NMR (400 MHz, DMSO-d6) methyl-6-(2-
.delta. 9.34 (d, J = 4.5 Hz, 1H), methylpyridin-4-yl)-4- 8.70 (dd,
J = 6.4, 0.6 Hz, 1H), 8.48 (d, (4H-1,2,4-triazol-3- J = 1.8 Hz,
1H), 8.44 (s, 1H), yl)benzimidazol-1- 8.25 (d, J = 1.9 Hz, 1H),
yl]quinoline 8.15 (dd, J = 6.3, 2.0 Hz, 1H), 8.10 (d, J = 4.5 Hz,
1H), 7.90 (d, J = 1.8 Hz, 1H), 7.79 (ddd, J = 10.0, 8.8, 4.2 Hz,
1H), 7.47 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.67 (s, 3H), 2.48 (s,
3H). 46 5,8-difluoro-4-[6-(2- 472.2 1H NMR (400 MHz, DMSO-d6)
fluoro-3-methylpyridin- .delta. 9.28 (d, J = 4.5 Hz, 1H),
4-yl)-2-methyl-4-(4H- 8.08 (d, J = 4.5 Hz, 1H), 8.03 (d, J = 5.0
Hz, 1,2,4-triazol-3- 1H), 7.95 (d, J = 1.6 Hz, yl)benzimidazol-1-
1H), 7.81-7.73 (m, 1H), yl]quinoline 7.51-7.44 (m, 1H), 7.38 (s,
1H), 7.24 (d, J = 5.0 Hz, 1H), 2.53 (s, 3H), 2.07 (s, 3H). 47
4-[6-(2,3- 462.1 1H NMR (400 MHz, DMSO-d6) difluoropyridin-4-yl)-4-
.delta. 9.26 (d, J = 4.5 Hz, 1H), (4H-1,2,4-triazol-3- 8.98 (d, J =
2.6 Hz, 1H), 8.37 (s, 1H), yl)benzimidazol-1-yl]- 8.29 (t, J = 1.6
Hz, 1H), 8.07 (d, 5,8-difluoroquinoline J = 4.6 Hz, 1H), 8.04 (dd,
J = 5.1, 1.1 Hz, 1H), 7.83 (d, J = 1.4 Hz, 1H), 7.82-7.74 (m, 1H),
7.61 (t, J = 5.1 Hz, 1H), 7.49 (ddd, J = 12.4, 8.8, 3.9 Hz, 1H).
143 4-(1-(5,7- 465.2 1H NMR (400 MHz, DMSO-d6)
difluoroquinolin-4-yl)- .delta. 9.31 (d, J = 4.6 Hz, 1H),
2-methyl-4-(4H-1,2,4- 8.72 (dd, J = 5.3, 0.8 Hz, 1H),
triazol-3-yl)-1H- 8.55-8.49 (m, 1H), 8.43 (d, J = 1.7 Hz,
benzo[d]imidazol-6- 1H), 8.40 (dd, J = 1.9, 0.8 Hz,
yl)picolinonitrile 1H), 8.09 (dd, J = 5.3, 2.0 Hz, 1H), 8.00 (ddd,
J = 9.7, 2.5, 1.3 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H), 7.86 (d, J =
1.7 Hz, 1H), 7.66 (ddd, J = 12.1, 9.3, 2.5 Hz, 1H), 2.52 (t, J =
0.5 Hz, 3H). 144 4-(1-(5-chloro-8- 481.1 1H NMR (400 MHz, DMSO-d6)
fluoroquinolin-4-yl)-2- .delta. 9.35 (d, J = 4.4 Hz, 1H),
methyl-4-(4H-1,2,4- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.51 (s,
triazol-3-yl)-1H- 1H), 8.45 (d, J = 1.8 Hz, 1H),
benzo[d]imidazol-6- 8.40 (dd, J = 1.9, 0.8 Hz, 1H),
yl)picolinonitrile 8.12-8.07 (m, 2H), 7.83 (d, J = 1.8 Hz, 1H),
7.81 (d, J = 1.4 Hz, 1H), 7.80 (s, 1H), 2.48 (s, 3H). 145
4-(1-(5,8- 497.1 1H NMR (400 MHz, DMSO-d6) dichloroquinolin-4-yl)-
.delta. 9.42 (d, J = 4.4 Hz, 1H), 2-methyl-4-(4H-1,2,4- 8.71 (dd, J
= 5.3, 0.8 Hz, 1H), 8.55 (s, triazol-3-yl)-1H- 1H), 8.46 (d, J =
1.7 Hz, 1H), benzo[d]imidazol-6- 8.40 (dd, J = 2.0, 0.8 Hz, 1H),
yl)picolinonitrile 8.15-8.07 (m, 3H), 7.86 (d, J = 1.7 Hz, 1H),
7.78 (d, J = 8.3 Hz, 1H), 2.50 (s, 3H). 146 4-(1-(5-chloroquinolin-
463.1 1H NMR (400 MHz, DMSO-d6) 4-yl)-2-methyl-4-(4H- .delta. 9.27
(d, J = 4.6 Hz, 1H), 1,2,4-triazol-3-yl)-1H- 8.70 (dd, J = 5.3, 0.8
Hz, 1H), 8.40 (d, benzo[d]imidazol-6- J = 1.8 Hz, 1H), 8.38 (dd, J
= 2.0, yl)picolinonitrile 0.8 Hz, 1H), 8.37-8.35 (m, 1H), 8.06 (dd,
J = 5.3, 1.9 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H), 7.73 (d, J = 1.8
Hz, 1H), 7.65 (dd, J = 9.0, 2.2 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H),
2.47 (s, 3H). 147 4-(1-(5-fluoroquinolin- 447.1 1H NMR (400 MHz,
DMSO-d6) 4-yl)-2-methyl-4-(4H- .delta. 9.30 (d, J = 4.5 Hz, 1H),
1,2,4-triazol-3-yl)-1H- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.57 (s,
benzo[d]imidazol-6- 1H), 8.46 (d, J = 1.7 Hz, 1H),
yl)picolinonitrile 8.41 (dd, J = 2.0, 0.8 Hz, 1H), 8.19-8.15 (m,
1H), 8.09 (dd, J = 5.3, 1.9 Hz, 1H), 8.00 (d, J = 4.6 Hz, 1H),
7.95-7.87 (m, 2H), 7.48 (ddd, J = 12.4, 7.9, 1.0 Hz, 1H), 2.53 (s,
3H). 148 4-(1-(8-fluoroquinolin- 447.1 1H NMR (400 MHz, DMSO-d6)
4-yl)-2-methyl-4-(4H- .delta. 9.30 (d, J = 4.5 Hz, 1H),
1,2,4-triazol-3-yl)-1H- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.58 (s,
benzo[d]imidazol-6- 1H), 8.48 (d, J = 1.7 Hz, 1H),
yl)picolinonitrile 8.39 (dd, J = 2.0, 0.8 Hz, 1H), 8.10-8.04 (m,
2H), 7.81 (d, J = 1.7 Hz, 1H), 7.76 (ddd, J = 10.8, 7.8, 1.2 Hz,
1H), 7.61 (td, J = 8.1, 5.0 Hz, 1H), 7.32-7.24 (m,
1H), 2.54 (s, 3H). 149 4-(1-(8-chloroquinolin- 463.0 1H NMR (400
MHz, DMSO-d6) 4-yl)-2-methyl-4-(4H- .delta. 9.36 (d, J = 4.5 Hz,
1H), 1,2,4-triazol-3-yl)-1H- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.58
(s, benzo[d]imidazol-6- 1H), 8.48 (d, J = 1.7 Hz, 1H),
yl)picolinonitrile 8.38 (dd, J = 2.0, 0.8 Hz, 1H), 8.11 (dd, J =
7.5, 1.2 Hz, 1H), 8.10-8.05 (m, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.60
(dd, J = 8.5, 7.5 Hz, 1H), 7.43 (dd, J = 8.5, 1.2 Hz, 1H), 2.53 (s,
3H). 150 4-(1-(8-chloro-5- 495.1 1H NMR (400 MHz, DMSO-d6)
fluoroquinolin-4-yl)-2- .delta. 9.41 (d, J = 4.5 Hz, 1H),
methyl-4-(5-methyl-4H- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.40 (d,
1,2,4-triazol-3-yl)-1H- J = 1.7 Hz, 1H), 8.38 (dd, J = 2.0,
benzo[d]imidazol-6- 0.8 Hz, 1H), 8.16-8.10 (m, yl)picolinonitrile
2H), 8.07 (dd, J = 5.3, 1.9 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.49
(dd, J = 12.0, 8.6 Hz, 1H), 2.53 (s, 3H), 2.51 (s, 3H). 151
4-(1-(5,8- 479.2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4-yl)-
.delta. 9.35 (d, J = 4.5 Hz, 1H), 2-methyl-4-(5-methyl- 8.71 (dd, J
= 5.3, 0.8 Hz, 1H), 4H-1,2,4-triazol-3-yl)- 8.42-8.37 (m, 2H), 8.10
(d, J = 4.5 Hz, 1H-benzo[d]imidazol-6- 1H), 8.08 (dd, J = 5.3, 2.0
Hz, yl)picolinonitrile 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.80 (ddd, J
= 10.0, 8.8, 4.2 Hz, 1H), 7.48 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H),
2.52 (s, 3H), 2.50 (s, 3H). 152 4-(1-(5,8- 466.1 1H NMR (400 MHz,
DMSO-d6) difluoroquinolin-4-yl)- .delta. 9.34 (d, J = 4.5 Hz, 1H),
2-methyl-4-(4H-1,2,4- 8.91 (d, J = 5.6 Hz, 1H), 8.87 (d, J = 1.7
Hz, triazol-3-yl)-1H- 1H), 8.43 (s, 1H), benzo[d]imidazol-6- 8.38
(d, J = 5.6 Hz, 1H), 8.11 (d, J = 4.5 Hz, yl)pyrimidine-2- 1H),
8.08 (d, J = 1.7 Hz, carbonitrile 1H), 7.83-7.76 (m, 1H), 7.47
(ddd, J = 12.3, 8.8, 3.8 Hz, 1H). 153 4-(1-(8-chloro-5- 481.1 1H
NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)-2- .delta. 9.42 (d, J =
4.5 Hz, 1H), methyl-4-(4H-1,2,4- 8.71 (dd, J = 5.3, 0.8 Hz, 1H),
8.53 (s, triazol-3-yl)-1H- 1H), 8.44 (d, J = 1.8 Hz, 1H),
benzo[d]imidazol-6- 8.39 (dd, J = 1.9, 0.8 Hz, 1H),
yl)picolinonitrile 8.16-8.11 (m, 2H), 8.08 (dd, J = 5.3, 1.9 Hz,
1H), 7.89 (d, J = 1.7 Hz, 1H), 7.49 (dd, J = 11.9, 8.6 Hz, 1H),
2.53 (s, 3H). 154 5,8-difluoro-4-(6-(2- 471.2 1H NMR (400 MHz,
DMSO-d6) methoxypyrimidin-4- .delta. 9.34 (d, J = 4.5 Hz, 1H),
yl)-2-methyl-4-(4H- 8.89 (d, J = 1.6 Hz, 1H), 8.56 (d, J = 5.3 Hz,
1,2,4-triazol-3-yl)-1H- 1H), 8.48 (s, 1H), benzo[d]imidazol-1- 8.12
(d, J = 4.5 Hz, 1H), 8.02 (d, J = 1.6 Hz, yl)quinoline 1H),
7.84-7.76 (m, 1H), 7.71 (d, J = 5.3 Hz, 1H), 7.48 (ddd, J = 12.4,
8.8, 3.8 Hz, 1H), 3.93 (s, 3H), 2.52 (s, 3H). 155
5,8-difluoro-4-(2- 455.2 1H NMR (400 MHz, DMSO-d6) methyl-6-(6-
.delta. 9.39 (d, J = 4.5 Hz, 1H), methylpyrimidin-4-yl)- 9.05 (d, J
= 1.3 Hz, 1H), 8.97 (d, J = 1.6 Hz, 4-(4H-1,2,4-triazol-3- 1H),
8.58 (s, 1H), yl)-1H- 8.16 (d, J = 4.5 Hz, 1H), 8.06 (d, J = 1.6
Hz, benzo[d]imidazol-1- 1H), 8.01 (dd, J = 1.3, yl)quinoline 0.6
Hz, 1H), 7.83 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H), 7.52 (ddd, J =
12.4, 8.8, 3.8 Hz, 1H), 2.57 (s, 3H), 2.47 (s, 3H). 156
5,8-difluoro-4-(2- 455.2 1H NMR (400 MHz, DMSO-d6) methyl-6-(2-
.delta. 9.37 (d, J = 4.5 Hz, 1H), methylpyrimidin-4-yl)- 8.95 (d, J
= 1.6 Hz, 1H), 8.67 (d, J = 5.5 Hz, 4-(4H-1,2,4-triazol-3- 1H),
8.52 (s, 1H), yl)-1H- 8.14 (d, J = 4.5 Hz, 1H), 8.06 (d, J = 1.6
Hz, benzo[d]imidazol-1- 1H), 7.90 (dd, J = 5.5, yl)quinoline 0.7
Hz, 1H), 7.82 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H), 7.50 (ddd, J =
12.4, 8.8, 3.8 Hz, 1H), 2.66 (s, 3H), 2.55 (s, 3H). 158
4-(6-(2-chloropyridin-4- 474.1 1H NMR (400 MHz, DMSO-d6)
yl)-2-methyl-4-(4H- .delta. 9.36 (d, J = 4.5 Hz, 1H),
1,2,4-triazol-3-yl)-1H- 8.51 (s, 1H), 8.41 (dd, J = 5.3, 0.6 Hz,
benzo[d]imidazol-1-yl)- 1H), 8.38 (dd, J = 1.8, 0.9 Hz,
5,8-difluoroquinoline 1H), 8.11 (d, J = 4.6 Hz, 1H), 7.88-7.75 (m,
4H), 7.50 (ddd, J = 12.3, 8.7, 3.8 Hz, 1H), 2.53 (d, J = 1.0 Hz,
3H). 159 5,8-difluoro-4-(6-(2- 458.2 1H NMR (400 MHz, DMSO-d6)
fluoropyridin-4-yl)-2- .delta. 9.35 (d, J = 4.5 Hz, 1H),
methyl-4-(4H-1,2,4- 8.50 (s, 1H), 8.42-8.37 (m, 1H),
triazol-3-yl)-1H- 8.25 (d, J = 5.3 Hz, 1H), 8.11 (d,
benzo[d]imidazol-1- J = 4.5 Hz, 1H), 7.87-7.84 (m, yl)quinoline
1H), 7.81 (ddd, J = 9.8, 8.8, 4.2 Hz, 1H), 7.73 (dt, J = 5.5, 1.8
Hz, 1H), 7.53 (s, 1H), 7.49 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.53
(s, 3H).
Preparation of Compounds of Formula (IM) in which
R.sup.30.dbd.NH.sub.2
A. Preparation of tert-butyl
(4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo-
[d]imidazol-6-yl)pyridin-2-yl)carbamate
##STR00223##
[0650] tert-Butyl
(4-(4-carbamoyl-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6--
yl)pyridin-2-yl)carbamate (120 mg, 0.23 mmol) was suspended in
1,1-dimethoxy-N,N-dimethylmethanamine (3.0 mL, 22.7 mmol) and
stirred at 100.degree. C. for 3 hours. The solution was cooled to
ambient temperature, concentrated under reduced pressure and dried
under vacuum for overnight. The residue was dissolved in acetic
acid (2 mL) and hydrazine (28 .mu.L, 0.57 mmol) was added. The
reaction mixture was stirred at 45.degree. C. for 1 hour, after
which the reaction was cooled to ambient temperature and
concentrated under reduced pressure. The resultant was purified by
HPLC eluting with 5-95% water/acetonitrile (0.1% v/v
trifluoroacetic acid). The appropriate fractions were pooled and
lyophilized to afford tert-butyl
(4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo-
[d]imidazol-6-yl)pyridin-2-yl)carbamate as a 2,2,2-trifluoroacetic
acid salt. ES/MS m/z=553.2 (M+H).sup.+.
[0651] tert-Butyl
(4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo-
[d]imidazol-6-yl)pyridin-2-yl)carbamate (35 mg of
2,2,2-trifluoroacetic acid salt, 0.06 mmol) was dissolved in
dichloromethane (0.6 mL) and trifluoroacetic acid (100 .mu.L, 2.93
mmol) was added. The reaction mixture was stirred at ambient
temperature for 1 hour, after which the reaction was concentrated
under reduced pressure. The resultant was dissolved in a mixture of
acetonitrile and water followed by lyophilization to afford
4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[-
d]imidazol-6-yl)pyridin-2-amine as a 2,2,2-trifluoroacetic acid
salt (Example 58).
[0652] The following compounds were prepared using a similar
procedure:
TABLE-US-00010 Example Name MS NMR 48 4-[3-(5,8-difluoroquinolin-
455.2 1H NMR (400 MHz, DMSO- 4-yl)-2-methyl-7-(4H- d6) .delta. 9.32
(d, J = 4.5 Hz, 1H), 1,2,4-triazol-3- 8.30 (d, J = 1.3 Hz, 1H),
yl)benzimidazol-5- 8.07 (d, J = 4.7 Hz, 1H), 7.89 (d, J = 6.8 Hz,
yl]pyridin-2-amine 1H), 7.87-7.74 (m, 4H), 7.69 (s, 1H), 7.52-7.36
(m, 1H), 7.26-7.19 (m, 2H). 49 4-[3-(8-chloroquinolin-4- 467.2 1H
NMR (400 MHz, DMSO- yl)-2-methyl-7-(5-methyl- d6) .delta. 9.34 (dt,
J = 4.6, 0.9 Hz, 4H-1,2,4-triazol-3- 1H), 8.31 (d, J = 1.9 Hz, 1H),
yl)benzimidazol-5- 8.13-8.08 (m, 1H), 8.05 (dd, yl]pyridin-2-amine
J = 4.6, 1.0 Hz, 1H), 7.87 (d, J = 7.0 Hz, 2H), 7.63-7.53 (m, 2H),
7.29 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.18 (d, J = 7.1 Hz, 1H).
50 4-[3-(8-chloro-5- 485.2 1H NMR (400 MHz, DMSO-
fluoroquinolin-4-yl)-2- d6) .delta. 9.38 (d, J = 4.5 Hz, 1H),
methyl-7-(5-methyl-4H- 8.29 (d, J = 1.8 Hz, 1H), 1,2,4-triazol-3-
8.12 (dd, J = 8.6, 5.0 Hz, 1H), yl)benzimidazol-5- 8.08 (d, J = 4.5
Hz, 1H), 7.88 (d, J = 6.8 Hz, yl]pyridin-2-amine 1H), 7.69 (d, J =
1.7 Hz, 1H), 7.48 (dd, J = 11.9, 8.5 Hz, 1H), 7.26 (s, 1H), 7.21
(d, J = 6.7 Hz, 1H), 2.46 (s, 3H), 2.45 (s, 3H). 51
4-[3-(8-chloro-5- 471.2 1H NMR (400 MHz, DMSO-
fluoroquinolin-4-yl)-2- d6) .delta. 9.39 (d, J = 4.5 Hz, 1H),
methyl-7-(4H-1,2,4-triazol- 8.44 (s, 1H), 8.33 (d, J = 1.7 Hz,
3-yl)benzimidazol-5- 1H), 8.13 (dd, J = 8.5, 5.0 Hz,
yl]pyridin-2-amine 1H), 8.09 (d, J = 4.5 Hz, 1H), 7.95 (s, 2H),
7.93 (s, 1H), 7.90 (d, J = 6.8 Hz, 7H), 7.74 (d, J = 1.8 Hz, 1H),
7.48 (dd, J = 11.9, 8.6 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.22
(dd, J = 6.9, 1.8 Hz, 2H), 3.18 (d, J = 46.3 Hz, 1H), 2.87 (s, 3H),
2.71 (s, 3H). 52 4-[2-ethyl-3-(7- 451.2 1H NMR (400 MHz, DMSO-
fluoroquinolin-4-yl)-7- d6) .delta. 9.25 (d, J = 4.6 Hz, 1H),
(4H-1,2,4-triazol-3- 8.44 (s, 1H), 8.35 (d, J = 1.8 Hz,
yl)benzimidazol-5- 1H), 8.06 (dd, J = 10.0, yl]pyridin-2-amine 2.6
Hz, 1H), 7.94 (d, J = 4.6 Hz, 1H), 7.89 (d, J = 6.5 Hz, 2H), 7.54
(d, J = 1.8 Hz, 1H), 7.41 (dd, J = 9.3, 6.0 Hz, 1H), 7.20 (dd, J =
8.4, 1.6 Hz, 2H), 2.72 (ddt, J = 23.9, 16.1, 7.9 Hz, 2H), 1.25 (t,
J = 7.5 Hz, 3H). 53 4-[3-(7-fluoroquinolin-4- 437.2 1H NMR (400
MHz, DMSO- yl)-2-methyl-7-(4H-1,2,4- d6) .delta. 9.26 (d, J = 4.5
Hz, 1H), triazol-3-yl)benzimidazol- 8.55 (s, 1H), 8.39 (d, J = 1.7
Hz, 5-yl]pyridin-2-amine 1H) 8.07 (dd, J = 10.1, 2.5 Hz, 1H),
8.00-7.89 (m, 2H), 7.62-7.45 (m, 3H), 7.24-7.16 (m, 2H), 2.52 (s,
3H). 54 4-[2-ethyl-3-(5- 451.2 1H NMR (400 MHz, DMSO-
fluoroquinolin-4-yl)-7- d6) .delta. 9.28 (d, J = 4.5 Hz, 1H),
(4H-1,2,4-triazol-3- 8.48 (s, 1H), 8.35 (d, J = 1.7 Hz,
yl)benzimidazol-5- 1H), 8.16 (dd, J = 8.6, 1.0 Hz,
yl]pyridin-2-amine 1H), 8.03-7.82 (m, 5H), 7.69 (d, J = 1.7 Hz,
1H), 7.50-7.42 (m, 1H), 7.23 (dd, J = 8.4, 1.5 Hz, 2H), 2.74 (qd, J
= 7.8, 4.7 Hz, 2H), 2.05 (s, 1H), 1.26 (t, J = 7.5 Hz, 3H). 55
4-[3-(5-fluoroquinolin-4- 437.2 1H NMR (400 MHz, DMSO-
yl)-2-methyl-7-(4H-1,2,4- d6) .delta. 9.28 (d, J = 4.5 Hz, 1H),
triazol-3-yl)benzimidazol- 8.47 (s, 1H), 8.34 (d, J = 1.7 Hz,
5-yl]pyridin-2-amine 1H), 8.19-8.12 (m, 1H), 7.97 (d, J = 4.5 Hz,
1H), 7.94-7.87 (m, 5H), 7.70 (d, J = 1.7 Hz, 1H), 7.47 (dd, J =
12.4, 7.8 Hz, 1H), 7.24 (d, J = 6.5 Hz, 2H). 56
4-[3-(8-chloroquinolin-4- 454.1 1H NMR (400 MHz, DMSO-
yl)-2-methyl-7-(4H-1,2,4- d6) .delta. 9.36 (d, J = 4.5 Hz, 1H),
triazol-3-yl)benzimidazol- 8.86 (d, J = 1.6 Hz, 1H),
5-yl]pyrimidin-2-amine 8.48 (s, 1H), 8.24 (d, J = 5.8 Hz, 1H) 8.12
(dd, J = 7.6, 1.2 Hz, 1H), 8.09 (d, J = 4.5 Hz, 1H), 7.87 (d, J =
1.6 Hz, 1H), 7.64-7.56 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.30 (d,
J = 5.8 Hz, 1H), 2.50 (s, 3H). 57 6-[3-(8-chloroquinolin-4- 469.1
1H NMR (400 MHz, DMSO- yl)-2-methyl-7-(4H-1,2,4- d6) .delta. 11.89
(s, 1H), 9.35 (d, J = 4.5 Hz, triazol-3-yl)benzimidazol- 1H), 8.44
(s, 1H), 5-yl]pyrimidine-2,4- 8.30 (s, 1H), 8.16-7.99 (m, diamine
4H), 7.61 (dd, J = 8.5, 7.6 Hz, 1H), 7.48 (s, 1H), 7.30 (dd, J =
8.6, 1.2 Hz, 1H), 6.29 (s, 1H), 2.47 (s, 3H). 58
4-[3-(8-chloroquinolin-4- 453.1 1H NMR (400 MHz, DMSO-
yl)-2-methyl-7-(4H-1,2,4- d6) .delta. 9.34 (d, J = 4.5 Hz, 1H),
triazol-3-yl)benzimidazol- 8.42 (s, 1H), 8.34 (d, J = 1.7 Hz,
5-yl]pyridin-2-amine 1H), 8.11 (dd, J = 7.5, 1.2 Hz, 1H), 8.06 (d,
J = 4.5 Hz, 1H), 7.89 (d, J = 6.9 Hz, 2H), 7.65-7.55 (m, 2H), 7.30
(dd, J = 8.5, 1.3 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.19 (dd, J =
6.8, 1.8 Hz, 1H), 2.47 (s, 3H). 59 6-[3-(8-chloroquinolin-4- 454.1
yl)-2-methyl-7-(4H-1,2,4- triazol-3-yl)benzimidazol-
5-yl]pyrimidin-4-amine 60 4-[2-cyclopropyl-3-(8- 463.2 1H NMR (400
MHz, DMSO- fluoroquinolin-4-yl)-7- d6) .delta. 9.28 (d, J = 4.5 Hz,
1H), (4H-1,2,4-triazol-3- 8.34 (d, J = 1.7 Hz, 1H),
yl)benzimidazol-5- 8.08 (d, J = 4.5 Hz, 1H), yl]pyridin-2-amine
7.91-7.86 (m, 1H), 7.83 (s, 2H), 7.76 (ddd, J = 10.8, 7.8, 1.2 Hz,
1H), 7.63 (td, J = 8.1, 5.0 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H),
7.25-7.16 (m, 3H), 1.65 (td, J = 8.2, 4.3 Hz, 1H), 1.60-1.41 (m,
2H), 1.08-0.97 (m, 1H), 0.98-0.88 (m, 1H). 61
4-[3-(8-fluoroquinolin-4- 437.2 1H NMR (400 MHz, DMSO-
yl)-2-methyl-7-(4H-1,2,4- d6) .delta. 9.27 (d, J = 4.5 Hz,
triazol-3-yl)benzimidazol- 1H), 8.34 (d, J = 1.8 Hz, 1H),
5-yl]pyridin-2-amine 8.05 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 6.9 Hz,
1H), 7.76 (ddd, J = 10.8, 7.7, 1.2 Hz, 1H), 7.61 (td, J = 8.1, 5.0
Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.23-7.21 (m, 1H), 7.19 (dd, J =
6.8, 1.9 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 2.47 (s, J = 0.7 Hz,
3H). 62 4-[3-(8-chloro-5- 497.2 1H NMR (400 MHz, DMSO-
fluoroquinolin-4-yl)-2- d6) .delta. 9.39 (d, J = 4.5 Hz, 1H),
cyclopropyl-7-(4H-1,2,4- 8.32 (d, J = 1.8 Hz, 1H),
triazol-3-yl)benzimidazol- 8.15-8.09 (m, 2H), 5-yl]pyridin-2-amine
7.91-7.86 (m, 1H), 7.82 (s, 2H), 7.69 (s, 1H), 7.49 (dd, J = 11.9,
8.6 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 6.9, 1.9 Hz,
1H), 1.71 (td, J = 8.2, 4.2 Hz, 1H), 1.49 (br s, 1H), 1.36 (br s,
1H), 1.04-0.88 (m, 2H). 63 4-[3-(8-chloro-5- 499.2 1H NMR (400 MHz,
DMSO- fluoroquinolin-4-yl)-2- d6) .delta. 9.38 (d, J = 4.5 Hz,
propyl-7-(4H-1,2,4-triazol- 1H), 8.31 (s, 1H), 8.12 (dd, J = 8.5,
3-yl)benzimidazol-5- 4.9 Hz, 1H), 8.08 (d, J = 4.5 Hz,
yl]pyridin-2-amine 1H), 7.88 (d, J = 6.7 Hz, 1H), 7.81 (br s, 1H),
7.68 (br s, 1H), 7.47 (dd, J = 11.9, 8.5 Hz, 1H), 7.24 (s, 1H),
7.21 (d, J = 6.7 Hz, 1H), 2.67 (t, J = 7.5 Hz, 2H), 1.85-1.75 (m,
2H), 0.85 (t, J = 7.4 Hz, 3H). 64 4-[3-(8-chloro-5- 511.1 1H NMR
(400 MHz, DMSO- fluoroquinolin-4-yl)-2- d6) .delta. 9.39 (d, J =
4.5 Hz, cyclopropyl-7-(5-methyl- 1H), 8.28 (d, J = 1.8 Hz, 1H),
4H-1,2,4-triazol-3- 8.15-8.09 (ABq, 2H), yl)benzimidazol-5-
7.92-7.85 (m, 3H), 7.68 (d, J = 1.8 Hz, yl]pyridin-2-amine 1H),
7.49 (dd, J = 11.9, 8.5 Hz, 1H), 7.27 (dd, J = 1.9, 0.7 Hz, 1H),
7.22 (dd, J = 6.9, 1.9 Hz, 1H), 2.42 (s, 3H), 1.71 (ddd, J = 12.9,
8.3, 4.8 Hz, 1H), 1.52-1.42 (m, 1H), 1.37-1.26 (m, 1H), 1.02-0.88
(m, 1H). 65 4-[3-(8-chloro-5- 513.2 1H NMR (400 MHz, DMSO-
fluoroquinolin-4-yl)-7-(5- d6) .delta. 9.38 (d, J = 4.5 Hz,
methyl-4H-1,2,4-triazol-3- 1H), 8.28 (d, J = 1.8 Hz, 1H),
yl)-2-propylbenzimidazol- 8.12 (dd, J = 8.6, 4.9 Hz, 1H),
5-yl]pyridin-2-amine 8.08 (d, J = 4.5 Hz, 1H), 7.87 (d, J = 6.9 Hz,
1H), 7.84 (s, 2H), 7.66 (s, 1H), 7.47 (dd, J = 11.9, 8.6 Hz, 1H),
7.25 (s, 1H), 7.21 (dd, J = 6.9, 1.8 Hz, 1H), 2.71-2.62 (m, 2H),
1.77-1.69 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 66 4-[3-(8-chloro-5-
513.2 1H NMR (400 MHz, DMSO- fluoroquinolin-4-yl)-7-(5- d6) .delta.
9.38 (d, J = 4.5 Hz, methyl-4H-1,2,4-triazol-3- 1H), 8.28 (d, J =
1.8 Hz, 1H), yl)-2-propan-2- 8.15-8.09 (m, 2H), 7.86 (d,
ylbenzimidazol-5- J = 6.8 Hz, 1H), 7.84 (s, 2H), yl]pyridin-2-amine
7.65 (s, 1H), 7.47 (dd, J = 11.9, 8.6 Hz, 1H), 7.25 (s, 1H), 7.21
(dd, J = 6.9, 1.8 Hz, 1H), 2.87 (p, J = 6.8 Hz, 1H), 2.44 (s, 3H),
1.31 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H). 67
4-[3-(8-chloro-5- 499.2 1H NMR (400 MHz, DMSO-
fluoroquinolin-4-yl)-2- d6) .delta. 9.39 (d, J = 4.5 Hz,
propan-2-yl-7-(4H-1,2,4- 1H), 8.32 (d, J = 1.8 Hz, 1H),
triazol-3-yl)benzimidazol- 8.16-8.09 (m, 2H), 7.88 (d,
5-yl]pyridin-2-amine J = 6.8 Hz, 1H), 7.84 (s, 2H), 7.68 (s, 1H),
7.48 (dd, J = 11.9, 8.5 Hz, 1H), 7.24 (s, 1H), 7.21 (dd, J = 6.9,
1.8 Hz, 1H), 2.88 (p, J = 6.7 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H),
1.26 (d, J = 6.8 Hz, 3H). 68 4-[3-(8-chloro-5- 513.1 1H NMR (400
MHz, DMSO- fluoroquinolin-4-yl)-2- d6) .delta. 9.36 (d, J = 4.5 Hz,
(oxetan-3-yl)-7-(4H-1,2,4- 1H), 8.37 (d, J = 1.8 Hz, 1H),
triazol-3-yl)benzimidazol- 8.12 (dd, J = 8.5, 4.9 Hz, 1H),
5-yl]pyridin-2-amine 8.01 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 6.8 Hz,
1H), 7.87 (s, 2H), 7.74 (s, 1H), 7.45 (dd, J = 12.0, 8.5 Hz, 1H),
7.28-7.24 (m, 1H), 7.22 (dd, J = 6.9, 1.9 Hz, 1H), 5.15 (s, 2H),
4.63 (ddd, J = 12.5, 8.6, 5.4 Hz, 2H), 4.34 (ddd, J = 15.6, 8.6,
7.0 Hz, 1H). 69 4-[2-cyclopropyl-3-(5,8- 481.2 1H NMR (400 MHz,
DMSO- difluoroquinolin-4-yl)-7- d6) .delta. 9.32 (d, J = 4.5 Hz,
(4H-1,2,4-triazol-3- 1H), 8.31 (d, J = 1.8 Hz, 1H),
yl)benzimidazol-5- 8.12 (d, J = 4.5 Hz, 1H), yl]pyridin-2-amine
7.92-7.83 (m, 3H), 7.82-7.75 (m, 1H), 7.69 (s, 1H), 7.48 (ddd, J =
12.3, 8.8, 3.8 Hz, 1H), 7.26-7.24 (m, 1H), 7.22 (dd, J = 6.9, 1.9
Hz, 1H), 1.71 (td, J = 8.2, 4.3 Hz, 1H), 1.50 (br s, 1H), 1.37 (br
s, 1H), 1.04-0.89 (m, 2H). 70 4-[3-(5,8-difluoroquinolin- 469.2 1H
NMR (400 MHz, DMSO- 4-yl)-2-ethyl-7-(4H-1,2,4- d6) .delta. 9.31 (d,
J = 4.5 Hz, triazol-3-yl)benzimidazol- 1H), 8.31 (d, J = 1.8 Hz,
1H), 5-yl]pyridin-2-amine 8.09 (d, J = 4.5 Hz, 1H), 7.90-7.79 (m,
3H), 7.78 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H), 7.69 (s, 1H), 7.46
(ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 7.25 (dd, J = 1.9, 0.7 Hz, 1H),
7.22 (dd, J = 6.9, 1.8 Hz, 1H), 2.77-2.64 (m, 2H), 1.28 (t, J = 7.5
Hz, 3H). 71 4-[2-(cyclopropylmethyl)- 495.2 1H NMR (400 MHz, DMSO-
3-(5,8-difluoroquinolin-4- d6) .delta. 9.31 (d, J = 4.5 Hz,
1H),
yl)-7-(4H-1,2,4-triazol-3- 8.32 (d, J = 1.7 Hz, 1H),
yl)benzimidazol-5- 8.08 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 6.8 Hz,
yl]pyridin-2-amine 1H), 7.87 (s, 2H), 7.83-7.72 (m, 1H), 7.69 (s,
1H), 7.44 (ddd, J = 12.3, 8.8, 3.9 Hz, 1H), 7.28-7.19 (m, 2H),
2.73-2.66 (m, 1H), 0.41-0.22 (m, 2H), 0.10-0.00 (m, 1H),
-0.04--0.13 (m, 1H). 72 4-[3-(5,8-difluoroquinolin- 483.2 1H NMR
(400 MHz, DMSO- 4-yl)-2-propyl-7-(4H- d6) .delta. 9.31 (d, J = 4.5
Hz, 1H), 1,2,4-triazol-3- 8.31 (d, J = 1.7 Hz, 1H),
yl)benzimidazol-5- 8.08 (d, J = 4.5 Hz, 1H), yl]pyridin-2-amine
7.90-7.88 (m, 1H), 7.86 (s, 2H), 7.82-7.75 (m, 1H), 7.68 (s, 1H),
7.46 (ddd, J = 12.3, 8.7, 3.7 Hz, 1H), 7.24 (t, J = 1.1 Hz, 1H),
7.22 (dd, J = 6.8, 1.9 Hz, 1H), 2.68 (t, J = 7.6 Hz, 2H), 1.84-1.73
(m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 73 4-[3-(8-chloroquinolin-4-
493.2 1H NMR (400 MHz, DMSO- yl)-2-(cyclopropylmethyl)- d6) .delta.
9.33 (d, J = 4.5 Hz, 1H), 7-(4H-1,2,4-triazol-3- 8.35 (d, J = 1.7
Hz, 1H), yl)benzimidazol-5- 8.10 (dd, J = 7.5, 1.2 Hz, 1H),
yl]pyridin-2-amine 8.07 (d, J = 4.5 Hz, 1H), 7.90-7.86 (m, 2H),
7.60-7.55 (m, 2H), 7.25-7.17 (m, 3H), 2.69 (d, J = 6.9 Hz, 2H),
0.37-0.29 (m, 1H), 0.28-0.19 (m, 1H), 0.09-0.02 (m, 1H), -0.8--0.14
(m, 1H). 74 4-[3-(8-chloroquinolin-4- 479.2 1H NMR (400 MHz, DMSO-
yl)-2-cyclopropyl-7-(4H- d6) .delta. 9.35 (d, J = 4.5 Hz, 1H),
1,2,4-triazol-3- 8.34 (s, 1H), 8.13-8.08 (m, yl)benzimidazol-5-
2H), 7.88 (d, J = 6.8 Hz, 1H), yl]pyridin-2-amine 7.81 (br s, 2H),
7.64-7.57 (m, 2H), 7.34 (dd, J = 8.4, 1.2 Hz, 1H), 7.23-7.18 (m,
2H), 1.69-1.61 (m, 1H), 1.06-0.98 (m, 2H), 0.96-0.88 (m, 2H).
Preparation of Compounds of Formula (IC) in which
R.sup.30.dbd.NH.sub.2
A. Preparation of
4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[-
d]imidazol-6-yl)-3-fluoropyridin-2-amine
##STR00224##
[0654]
1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H--
benzo[d]imidazole-4-carboxamide (130 mg, 0.29 mmol) was suspended
in 1,1-dimethoxy-N,N-dimethylmethanamine (1.9 mL, 14.4 mmol) and
stirred at 100.degree. C. for 3 hours. The solution was cooled to
ambient temperature, concentrated under reduced pressure and dried
under vacuum for overnight. The residue was dissolved in acetic
acid (3 mL) and hydrazine (18 .mu.L, 0.58 mmol) was added. The
reaction mixture was stirred at 45.degree. C. for 1 hour, after
which the reaction was cooled to ambient temperature and
concentrated under reduced pressure. The residue was taken up in
ethyl acetate, washed with saturated NaHCO.sub.3, washed with
brine, dried with magnesium sulfate, filtered, and concentrated
under reduced pressure. Crude
8-chloro-4-(6-(2,3-difluoropyridin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-y-
l)-1H-benzo[d]imidazol-1-yl)quinoline was used without further
purification in the next step. ES/MS m/z 474.2 (M+H).sup.+.
[0655] Ammonium hydroxide (28-30% solution in water, 0.75 mL) was
added to a solution of crude
8-chloro-4-(6-(2,3-difluoropyridin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-y-
l)-1H-benzo[d]imidazol-1-yl)quinoline (0.274 mmol) in DMSO (3.0
mL). The reaction vessel was sealed and the reaction mixture was
stirred at 100.degree. C. overnight. The excess ammonia was removed
under reduced pressure and the resulting solution was purified by
HPLC eluting with 5-95% water/acetonitrile (0.1% v/v
trifluoroacetic acid). The appropriate fractions were pooled and
lyophilized to afford
4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[-
d]imidazol-6-yl)-3-fluoropyridin-2-amine as a 2,2,2-trifluoroacetic
acid salt (Example 80).
[0656] The following compounds were synthesized using a similar
method: [0657] tert-butyl
4-(4-(6-(2-amino-3-fluoropyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo-
[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate
TABLE-US-00011 [0657] Example Name MS NMR 75 4-[3-(5,8- 473.2 1H
NMR (400 MHz, DMSO-d6) difluoroquinolin-4- .delta. 9.31 (d, J = 4.5
Hz, 1H), yl)-2-methyl-7-(4H- 8.41 (br s, 1H), 8.22 (s, 1H), 8.09
(d, J = 4.5 Hz, 1,2,4-triazol-3- 1H), 7.78 (td, J = 9.5,
yl)benzimidazol-5- 4.2 Hz, 1H), 7.74 (dd, J = 6.2, 0.9 Hz,
yl]-3-fluoropyridin-2- 1H), 7.52 (s, 1H), 7.47 (ddd, J = 12.3,
amine 8.8, 3.8 Hz, 1H), 6.84 (br s, 1H), 2.51 (s, 3H). 76
4-[3-(5,8- 473.2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4-
.delta. 9.31 (d, J = 4.5 Hz, 1H), yl)-2-methyl-7-(4H- 8.42 (br s,
1H), 8.17 (t, J = 1.8 Hz, 1,2,4-triazol-3- 1H), 8.10 (s, 1H), 8.09
(s, 1H), yl)benzimidazol-5- 7.83-7.75 (m, 1H),
yl]-5-fluoropyridin-2- 7.53-7.43 (m, 2H), 6.82 (d, J = 6.0 Hz, 1H),
amine 2.50 (s, 3H). 77 4-[3-(5,8- 487.2 1H NMR (400 MHz, DMSO-d6)
difluoroquinolin-4- .delta. 9.31 (d, J = 4.5 Hz, 1H),
yl)-2-methyl-7-(4H- 8.47 (s, 1H), 8.23 (t, J = 1.6 Hz, 1H),
1,2,4-triazol-3- 8.10 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5-
7.83-7.75 (m, 2H), 7.53 (s, 1H), yl]-3-fluoro-N- 7.48 (ddd, J =
12.3, 8.8, 3.8 Hz, 1H), methylpyridin-2- 6.74 (t, J = 5.6 Hz, 1H),
2.87 (s, amine 3H), 2.53 (s, 3H). 78 4-[3-(5,8- 501.2 1H NMR (400
MHz, DMSO-d6) difluoroquinolin-4- .delta. 9.30 (d, J = 4.5 Hz, 1H),
yl)-2-propyl-7-(4H- 8.37 (br s, 1H), 8.20 (d, J = 1.5 Hz,
1,2,4-triazol-3- 1H), 8.09 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5-
7.81-7.74 (m, 1H), 7.72 (d, J = 6.0 Hz, yl]-3-fluoropyridin-2- 1H),
7.50-7.43 (m, 2H), amine 6.83 (t, J = 5.8 Hz, 1H), 2.71 (t, J = 7.5
Hz, 2H), 1.82-1.72 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 79 4-[3-(8-
497.2 1H NMR (400 MHz, DMSO-d6) chloroquinolin-4-yl)- .delta. 9.33
(d, J = 4.5 Hz, 1H), 8.28 (s, 2-cyclopropyl-7-(4H- 1H), 8.23 (t, J
= 1.5 Hz, 1H), 1,2,4-triazol-3- 8.13-8.08 (m, 2H), 7.72 (d, J = 6.2
Hz, yl)benzimidazol-5- 1H), 7.62 (dd, J = 8.5, 7.5 Hz,
yl]-3-fluoropyridin-2- 1H), 7.39 (s, 1H), 7.36 (dd, J = 8.5, amine
1.2 Hz, 1H), 6.86 (t, J = 6.0 Hz, 1H), 1.71-1.63 (m, 1H), 1.53 (br
s, 1H), 1.46 (br s, 1H), 1.07-0.97 (m, 1H), 0.97-0.87 (m, 1H). 80
4-[3-(8- 471.2 1H NMR (400 MHz, DMSO-d6) chloroquinolin-4-yl)-
.delta. 9.33 (d, J = 4.5 Hz, 1H), 8.25 (t, 2-methyl-7-(4H- J = 1.5
Hz, 1H), 8.11 (dd, J = 7.5, 1,2,4-triazol-3- 1.2 Hz, 1H), 8.07 (d,
J = 4.5 Hz, yl)benzimidazol-5- 1H), 7.72 (d, J = 6.0 Hz, 1H),
yl]-3-fluoropyridin-2- 7.60 (dd, J = 8.5, 7.5 Hz, 1H), amine 7.41
(s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 5.8 Hz, 1H), 2.51
(s, 3H). 81 4-[2-cyclopropyl-3- 499.2 1H NMR (400 MHz, DMSO-d6)
(5,8- .delta. 9.30 (d, J = 4.5 Hz, 1H), 8.26 (s,
difluoroquinolin-4- 1H), 8.20 (d, J = 1.7 Hz, 1H), yl)-7-(4H-1,2,4-
8.12 (d, J = 4.5 Hz, 1H), triazol-3- 7.81-7.74 (m, 1H), 7.73 (d, J
= 6.1 Hz, yl)benzimidazol-5- 1H), 7.51-7.44 (m, 2H), 6.86 (t,
yl]-3-fluoropyridin-2- J = 5.9 Hz, 1H), 1.72 (td, J = 8.2, amine
4.2 Hz, 1H), 1.50 (br s, 1H), 1.38 (br s, 1H), 1.02-0.89 (m, 1H).
82 4-[3-(5,8- 487 2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4-
.delta. 9.31 (d, J = 4.5 Hz, 1H), 8.43 (s, yl)-2-methyl-7-(4H- 1H),
8.16 (t, J = 1.7 Hz, 1H), 1,2,4-triazol-3- 8.10 (d, J = 4.5 Hz,
1H), 8.04 (d, J = 3.3 Hz, yl)benzimidazol-5- 1H), 7.79 (td, J =
9.5, 4.2 Hz, yl]-5-fluoro-N- 1H), 7.53-7.43 (m, 2H),
methylpyridin-2- 6.65 (d, J = 5.7 Hz, 1H), 2.76 (s, amine 3H), 2.51
(s, 3H). 83 4-[3-(8-chloro-5- 489.2 1H NMR (400 MHz, DMSO-d6)
fluoroquinolin-4-yl)- .delta. 9.38 (d, J = 4.5 Hz, 1H), 8.42 (s,
2-methyl-7-(4H- 1H), 8.25-8.21 (m, 1H), 1,2,4-triazol-3- 8.15-8.09
(m, 2H), 7.73 (d, J = 6.0 Hz, yl)benzimidazol-5- 1H), 7.54 (s, 1H),
7.48 (dd, J = 11.9, yl]-3-fluoropyridin-2- 8.6 Hz, 1H), 6.85 (t, J
= 5.8 Hz, amine 1H), 2.50 (s, 3H). 84 4-[3-(8-chloro-5- 417.2 1H
NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)- .delta. 9.37 (d, J =
4.5 Hz, 1H), 8.36 (s, 2-propyl-7-(4H- 1H), 8.20 (s, 1H), 8.15-8.08
(m, 1,2,4-triazol-3- 2H), 7.72 (d, J = 6.0 Hz, 1H),
yl)benzimidazol-5- 7.51-7.42 (m, 2H), 6.83 (t, J = 5.8 Hz,
yl]-3-fluoropyridin-2- 1H), 2.71 (t, J = 7.6 Hz, amine 2H),
1.82-1.73 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 85 4-[3-(8-chloro-5-
515.2 1H NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)- .delta. 9.37
(d, J = 4.5 Hz, 1H), 8.26 (s, 2-cyclopropyl-7-(4H- 1H), 8.21 (s,
1H), 8.14-8.10 (m, 1,2,4-triazol-3- 2H), 7.73 (d, J = 6.1 Hz, 1H),
yl)benzimidazol-5- 7.53-7.45 (m, 2H), 6.87 (t, J = 5.9 Hz,
yl]-3-fluoropyridin-2- 1H), 1.77-1.68 (m, 1H), amine 1.50 (br s,
1H), 1.37 (br s, 1H), 1.02-0.88 (m, 1H). 86 3-fluoro-4-[3-(8- 455.2
1H NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)- .delta. 9.27 (d, J
= 4.5 Hz, 1H), 8.53 (s, 2-methyl-7-(4H- 1H), 8.29 (t, J = 1.5 Hz,
1H), 1,2,4-triazol-3- 8.07 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5-
7.80-7.73 (m, 2H), 7.62 (td, J = 8.1, 5.0 Hz, yl]pyridin-2-amine
1H), 7.46 (t, J = 1.3 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.89 (t, J
= 6.1 Hz, 1H), 2.55 (s, 3H). 87 3-fluoro-4-[3-(8- 483.2 1H NMR (400
MHz, DMSO-d6) fluoroquinolin-4-yl)- .delta. 9.26 (d, J = 4.5 Hz,
1H), 8.43 (s, 2-propyl-7-(4H- 1H), 8.25 (t, J = 1.5 Hz, 1H),
1,2,4-triazol-3- 8.07 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5-
7.79-7.72 (m, 2H), 7.61 (td, J = 8.2, 5.0 Hz, yl]pyridin-2-amine
1H), 7.39 (t, J = 1.3 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.87 (t, J
= 6.0 Hz, 1H), 2.73 (dd, J = 8.2, 6.8 Hz, 2H), 1.73 (qt, J = 8.6,
4.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H). 88 4-[2-cyclopropyl-3- 481.2
1H NMR (400 MHz, DMSO-d6) (8-fluoroquinolin-4- .delta. 9.26 (d, J =
4.5 Hz, 1H), 8.29 (s, yl)-7-(4H-1,2,4- 1H), 8.23 (t, J = 1.5 Hz,
1H), triazol-3- 8.08 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5-
7.79-7.71 (m, 2H), 7.63 (td, J = 8.1, 5.0 Hz,
yl]-3-fluoropyridin-2- 1H), 7.39 (t, J = 1.3 Hz, 1H), amine
7.25-7.19 (m, 1H), 6.89 (t, J = 6.0 Hz, 1H), 1.67 (td, J = 8.2, 4.3
Hz, 1H), 1.57-1.42 (m, 2H), 1.07-1.00 (m, 1H), 0.99-0.87 (m, 1H).
89 4-[3-(8-chloro-3- 485.2 1H NMR (400 MHz, DMSO-d6)
methylquinolin-4-yl)- .delta. 9.27 (d, J = 0.5 Hz, 1H), 8.43 (s,
2-methyl-7-(4H- 1H), 8.25-8.23 (m, 1H), 1,2,4-triazol-3- 8.02 (dd,
J = 7.5, 1.2 Hz, 1H), 7.72 (d, yl)benzimidazol-5- J = 6.1 Hz, 1H),
7.55 (dd, J = 8.5, yl]-3-fluoropyridin-2- 7.5 Hz, 1H), 7.39 (s,
1H), amine 7.11 (dd, J = 8.4, 1.2 Hz, 1H), 6.85 (t, J = 5.8 Hz,
1H), 2.41 (s, 3H), 2.20 (s, 3H). 90 4-[3-(5,8- 469.2 1H NMR (400
MHz, DMSO-d6) difluoroquinolin-4- .delta. 9.33 (d, J = 4.5 Hz, 1H),
yl)-2-methyl-7-(4H- 8.30 (d, J = 1.7 Hz, 1H), 8.08 (d, J = 4.5 Hz,
1,2,4-triazol-3- 1H), 7.84-7.75 (m, 1H), yl)benzimidazol-5- 7.64
(s, 1H), 7.60 (s, 2H), yl]-6-methylpyridin- 7.47 (ddd, J = 12.3,
8.8, 3.8 Hz, 1H), 2-amine 7.10 (s, 1H), 7.06 (s, 1H), 2.45 (s, 3H),
2.39 (s, 3H). 91 3-chloro-4-[3-(5,8- 489.2 1H NMR (400 MHz,
DMSO-d6) difluoroquinolin-4- .delta. 9.30 (d, J = 4.5 Hz, 1H), 8.47
(s, yl)-2-methyl-7-(4H- 1H), 8.10 (d, J = 4.5 Hz, 1H),
1,2,4-triazol-3- 8.07 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 5.6 Hz,
yl)benzimidazol-5- 1H), 7.78 (td, J = 9.4, yl]pyridin-2-amine 4.2
Hz, 1H), 7.49 (ddd, J = 12.4, 8.9, 3.8 Hz, 1H), 7.41 (d, J = 1.6
Hz, 1H), 6.70 (d, J = 5.6 Hz, 1H), 2.55 (s, 3H). 92
4-[3-(3-chloro-8- 489.2 1H NMR (400 MHz, DMSO-d6)
fluoroquinolin-4-yl)- .delta. 9.35 (s, 1H), 8.39 (s, 1H),
2-methyl-7-(4H- 8.22 (t, J = 1.5 Hz, 1H), 7.79 (ddd, J = 10.7,
1,2,4-triazol-3- 7.8, 1.2 Hz, 1H), 7.73 (d, J = 6.0 Hz,
yl)benzimidazol-5- 1H), 7.67 (td, J = 8.2, 5.0 Hz,
yl]-3-fluoropyridin-2- 1H), 7.51 (s, 1H), 7.13 (d, J = 8.4 Hz,
amine 2H), 6.83 (t, J = 5.9 Hz, 1H), 2.43 (s, 3H). 93
3-fluoro-4-[3-(5- 455.2 1H NMR (400 MHz, DMSO-d6)
fluoroquinolin-4-yl)- .delta. 9.26 (d, J = 4.5 Hz, 1H),
2-methyl-7-(4H- 8.44 (br s, 1H), 8.23 (t, J = 1.5 Hz,
1,2,4-triazol-3- 1H), 8.15 (dd, J = 8.6, 1.0 Hz, yl)benzimidazol-5-
1H), 7.98 (d, J = 4.6 Hz, 1H), yl]pyridin-2-amine 7.91 (td, J =
8.3, 5.7 Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), 7.51-7.43 (m, 2H), 6.87
(t, J = 5.9 Hz, 1H), 2.51 (s, 3H). 94 4-[2-ethyl-3-(5- 469.2 1H NMR
(400 MHz, DMSO-d6) fluoroquinolin-4-yl)- .delta. 9.26 (d, J = 4.5
Hz, 1H), 8.40 (s, 7-(4H-1,2,4-triazol-3- 1H), 8.23 (t, J = 1.5 Hz,
1H), yl)benzimidazol-5- 8.17-8.13 (m, 1H), 7.99 (d, J = 4.5 Hz,
yl]-3-fluoropyridin-2- 1H), 7.90 (ddd, J = 8.6, 7.9, amine 5.7 Hz,
1H), 7.75 (d, J = 6.3 Hz, 1H), 7.50-7.42 (m, 2H), 6.92 (t, J = 6.1
Hz, 1H), 2.75 (qd, J = 7.7, 4.7 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H).
95 4-[3-(5,8- 487.2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4-
.delta. 9.30 (d, J = 4.5 Hz, 1H), 8.38 (s, yl)-2-ethyl-7-(4H- 1H),
8.22 (s, 1H), 8.10 (d, J = 4.5 Hz, 1,2,4-triazol-3- 1H), 7.83-7.71
(m, 2H), yl)benzimidazol-5- 7.51 (t, J = 1.2 Hz, 1H),
yl]-3-fluoropyridin-2- 7.46 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), amine
6.89 (t, J = 6.0 Hz, 1H), 2.81-2.68 (m, 2H), 1.27 (t, J = 7.5 Hz,
3H). 96 4-[2- 513.2 1H NMR (400 MHz, DMSO-d6) (cyclopropylmethyl)-
.delta. 9.29 (d, J = 4.5 Hz, 1H), 3-(5,8- 8.37 (br s, 1H), 8.21 (d,
J = 1.6 Hz, difluoroquinolin-4- 1H), 8.09 (d, J = 4.5 Hz, 1H),
yl)-7-(4H-1,2,4- 7.81-7.71 (m, 2H), triazol-3- 7.51-7.41 (m, 2H),
6.84 (t, J = 5.8 Hz, 1H), yl)benzimidazol-5- 2.73 (dd, J = 6.9, 4.1
Hz, 2H), yl]-3-fluoropyridin-2- 1.07 (br s, 1H), 0.40-0.22 (m,
amine 2H), 0.12--0.14 (m, 2H). 97 4-[3-(5,8- 487.2 1H NMR (400 MHz,
DMSO-d6) difluoroquinolin-4- .delta. 9.31 (d, J = 4.5 Hz, 1H), 8.22
(t, yl)-2-methyl-7-(5- J = 1.6 Hz, 1H), 8.09 (d, J = 4.5 Hz,
methyl-4H-1,2,4- 1H), 7.83-7.76 (m, 1H), triazol-3- 7.74 (d, J =
6.0 Hz, 1H), 7.53 (d, J = 1.5 Hz, yl)benzimidazol-5- 1H), 7.48
(ddd, J = 12.4, yl-]3-fluoropyridin-2- 8.8, 3.8 Hz, 1H), 6.85 (t, J
= 5.9 Hz, amine 1H), 2.52 (s, 3H), 2.47 (s, 3H). 98
4-[3-(8-chloro-5- 503.2 1H NMR (400 MHz, DMSO-d6)
fluoroquinolin-4-yl)- .delta. 9.39 (d, J = 4.5 Hz, 1H), 8.25 (t,
2-methyl-7-(5- J = 1.6 Hz, 1H), 8.16-8.10 (m, methyl-4H-1,2,4- 2H),
7.75 (d, J = 6.2 Hz, 1H), triazol-3- 7.59 (dd, J = 1.7, 0.9 Hz,
1H), yl)benzimidazol-5- 7.49 (dd, J = 11.9, 8.6 Hz, 1H),
yl]-3-fluoropyridin-2- 6.89 (t, J = 6.0 Hz, 1H), 2.54 (s, amine
3H), 2.49 (s, 3H). 99 4-[3-(5-chloro-8- 489.1 1H NMR (400 MHz,
DMSO-d6) fluoroquinolin-4-yl)- .delta. 9.27 (d, J = 4.4 Hz, 1H),
8.15 (s, 2-methyl-7-(4H- 1H), 8.00 (d, J = 4.8 Hz, 1H),
1,2,4-triazol-3- 7.80-7.74 (m, 2H), 7.68 (d, J = 5.2 Hz,
yl)benzimidazol-5- 1H), 7.11 (s, 1H), 6.59 (t,
yl]-3-fluoropyridin-2- J = 5.3 Hz, 1H), 6.16 (s, 2H), amine 2.36
(s, 3H). 100 4-[3-(5,8- 491.1 1H NMR (400 MHz, DMSO-d6)
difluoroquinolin-4- .delta. 9.30 (d, J = 4.5 Hz, 1H), 8.47 (s,
yl)-2-methyl-7-(4H- 1H), 8.10 (d, J = 4.6 Hz, 1H), 1,2,4-triazol-3-
8.06 (d, J = 1.4 Hz, 1H), 7.87 (t, J = 0.6 Hz, yl)benzimidazol-5-
1H), 7.82-7.75 (m, yl]-3,5- 1H), 7.52-7.44 (m, 2H), 2.55 (s,
difluoropyridin-2- 3H). amine 101 4-[3-(5,8- 469.2 1H NMR (400 MHz,
DMSO-d6) difluoroquinolin-4- .delta. 9.28 (d, J = 4.5 Hz, 1H),
yl)-2-methyl-7-(4H- 8.06 (d, J = 4.5 Hz, 1H), 7.88 (d, J = 1.6 Hz,
1,2,4-triazol-3- 1H), 7.84-7.74 (m, 4H), yl)benzimidazol-5- 7.47
(ddd, J = 12.3, 8.8, 3.9 Hz, yl]-3-methylpyridin- 1H), 7.29 (s,
1H), 6.83 (d, J = 6.6 Hz, 2-amine 1H), 1.99 (s, 3H). 102 4-[3-(5,8-
459.1 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4- .delta. 9.24
(d, J = 4.6 Hz, 1H), 8.91 (s, yl)-7-(4H-1,2,4- 1H), 8.21 (s, 1H),
8.06 (d, J = 4.6 Hz, triazol-3- 1H), 7.78 (ddd, J = 10.1, 8.8,
yl)benzimidazol-5- 4.2 Hz, 1H), 7.73 (d, J = 5.3 Hz,
yl]-3-fluoropyridin-2- 1H), 7.66 (s, 1H), 7.48 (ddd, J = 12.4,
amine 8.8, 3.9 Hz, 1H), 6.68 (t, J = 5.2 Hz, 1H), 6.30 (s, 2H). 160
4-(1-(5,7- 473.2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4-
.delta. 9.28 (d, J = 4.6 Hz, 1H), 8.41 (s, yl)-2-methyl-4-(4H- 1H),
8.22 (t, J = 1.6 Hz, 1H), 1,2,4-triazol-3-yl)- 8.01-7.94 (m, 2H),
7.74 (d, J = 6.0 Hz, 1H- 1H), 7.66 (ddd, J = 12.0, 9.2,
benzo[d]imidazol-6- 2.5 Hz, 1H), 7.49 (s, 1H), 6.85 (t,
yl)-3-fluoropyridin-2- J = 5.8 Hz, 1H), 2.51 (s, 3H).
amine 161 4-(1-(5,8- 505.1 1H NMR (400 MHz, DMSO-d6)
dichloroquinolin-4- .delta. 9.38 (d, J = 4.4 Hz, 1H), 8.45 (s,
yl)-2-methyl-4-(4H- 1H), 8.25 (t, J = 1.6 Hz, 1H),
1,2,4-triazol-3-yl)- 8.12 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 4.4 Hz,
1H- 1H), 7.78 (d, J = 8.3 Hz, benzo[d]imidazol-6- 1H), 7.74 (d, J =
6.2 Hz, 1H), yl)-3-fluoropyridin-2- 7.53-7.49 (m, 1H), 6.88 (t, J =
6.0 Hz, amine 1H), 2.48 (s, 3H).
A. Preparation of
4-(6-(2,3-difluoropyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imid-
azol-1-yl)-2-(piperazin-1-yl)quinoline
##STR00225##
[0659] To a solution of tert-butyl
4-(4-(6-(2,3-difluoropyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]i-
midazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate (41 mg, 0.07
mmol) in DCM (1.0 mL) was added TFA (0.2 mL). The mixture was then
stirred for 1 hour. After concentration under reduced pressure, the
resultant was purified by HPLC eluting with 5-95%
water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriate
fractions were pooled and lyophilized to afford
4-(6-(2,3-difluoropyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imid-
azol-1-yl)-2-(piperazin-1-yl)quinoline as a 2,2,2-trifluoroacetic
acid salt. ES/MS m/z=510.2 (M+H)+ (Example 164)
[0660] The following compounds were synthesized using a similar
method:
TABLE-US-00012 Example Name MS NMR 162 3-fluoro-4-(1-(2- 507.3 1H
NMR (400 MHz, DMSO-d6) (piperazin-1- .delta. 8.96 (s, 1H), 8.91 (s,
0H), 8.37 yl)quinolin-4-yl)-4- (s, 1H), 8.27 (t, J = 1.5 Hz, 1H),
(4H-1,2,4-triazol-3- 7.82-7.73 (m, 3H), 7.70 (ddd, J = yl)-1H- 8.4,
5.7, 2.7 Hz, 1H), 7.59 (d, J = benzo[d]imidazol-6- 1.6 Hz, 1H),
7.34-7.26 (m, yl)pyridin-2-amine 2H), 6.85 (t, J = 5.7 Hz, 1H),
3.98 (s, 4H), 3.24 (s, 4H). 163 3-fluoro-4-(1-(2- 440.2 1H NMR (400
MHz, DMSO-d6) (piperazin-1- .delta. 8.92 (s, 2H), 8.75 (s, 1H),
8.01 yl)quinolin-4-yl)-1H- (dd, J = 8.5, 0.6 Hz, 1H), 7.81-
benzo[d]imidazol-6- 7.74 (m, 2H), 7.72-7.65 (m, yl)pyridin-2-amine
2H), 7.63 (dt, J = 8.5, 1.6 Hz, 1H), 7.49 (s, 1H), 7.32-7.22 (m,
2H), 6.85 (t, J = 5.9 Hz, 1H), 3.97 (s, 4H), 3.23 (s, 4H). 164
4-(6-(2,3- 510.2 1H NMR (400 MHz, DMSO-d6) difluoropyridin-4-yl)-
.delta. 8.96 (s, 1H), 8.85 (s, 3H), 8.37 4-(4H-1,2,4-triazol-3- (s,
1H), 8.29 (t, J = 1.6 Hz, 1H), yl)-1H- 8.05 (dd, J = 5.1, 1.1 Hz,
1H), benzo[d]imidazol-1- 7.79 (dt, J = 8.5, 1.0 Hz, 1H),
yl)-2-(piperazin-1- 7.75 (s, 1H), 7.73-7.67 (m, 2H), yl)quinoline
7.61 (t, J = 5.1 Hz, 1H), 7.32- 7.28 (m, 2H), 3.98 (s, 4H), 3.24
(s, 4H). 165 4-(6-(2,3- 443.2 1H NMR (400 MHz, DMSO-d6)
difluoropyridin-4-yl)- .delta. 8.91 (s, 2H), 8.77 (d, J = 0.4 1H-
Hz, 1H), 8.05-8.01 (m, 2H), benzo[d]imidazol-1- 7.80-7.76 (m, 1H),
7.73-7.64 (m, yl)-2-(piperazin-1- 4H), 7.60-7.57 (m, 1H), 7.55 (t,
yl)quinoline J = 5.1 Hz, 1H), 7.33-7.24 (m, 2H), 3.97 (s, 4H), 3.23
(s, 4H). 166 4-(1-(2-(1H-pyrazol- 481.2 1H NMR (400 MHz, DMSO-d6)
4-yl)quinolin-4-yl)-4- .delta. 9.05 (s, 1H), 8.72 (dd, J = 5.3,
(4H-1,2,4-triazol-3- 0.7 Hz, 1H), 8.49-8.43 (m, 4H), yl)-1H- 8.33
(s, 1H), 8.18-8.15 (m, 1H), benzo[d]imidazol-6- 8.11 (dd, J = 5.3,
1.9 Hz, 1H), yl)picolinonitrile 8.02 (d, J = 1.7 Hz, 1H), 7.87-
7.81 (m, 1H), 7.53 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.42 (d, J =
8.3 Hz, 1H). 167 4-(1-(2-(piperazin-1- 499.2 1H NMR (400 MHz,
DMSO-d6) yl)quinolin-4-yl)-4- .delta. 8.93 (s, 1H), 8.86 (s, 2H),
8.74 (4H-1,2,4-triazol-3- (dd, J = 5.2, 0.8 Hz, 1H), 8.47- yl)-1H-
8.42 (m, 2H), 8.38 (s, 1H), 8.11 benzo[d]imidazol-6- (dd, J = 5.3,
1.9 Hz, 1H), 7.99 (d, yl)picolinonitrile J = 1.8 Hz, 1H), 7.81 (dt,
J = 8.5, 0.9 Hz, 1H), 7.75 (s, 1H), 7.70 (ddd, J = 8.4, 6.4, 1.9
Hz, 1H), 7.34-7.23 (m, 2H), 3.99 (s, 4H), 3.25 (s, 4H).
Separation of Atropisomers of Compounds of Formula (IM)
A. Separation of the Atropisomers of
4-(1-(5,8-difluoroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-be-
nzo[d]imidazol-6-yl)pyridin-2-amine
##STR00226##
[0662] The atropisomers of Example 48 were separated on OD-H SFC 5
.mu.M 21.times.250 mm column in 30% EtOH/CO.sub.2 at 60 mL/min to
give the two single atropisomers of
4-(1-(5,8-difluoroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-be-
nzo[d]imidazol-6-yl)pyridin-2-amine (Example 103 and Example
104).
[0663] The following compounds were prepared using a similar
procedure:
TABLE-US-00013 Separation Peak Ex- Name method # ample MS NMR
4-(1-(5,8- OD-H SFC 1.sup.st 103 455.2 1H NMR difluoroquinolin- 5
uM e- (400 MHz, 4-yl)-2-methyl- 21 .times. luting DMSO-d6) .delta.
9.32 4-(4H-1,2,4- 250 mm peak (d, J = 4.5 Hz, 1H), triazol-3-yl)-
column in 8.30 (d, J = 1.3 Hz, 1H- 30% 1H), 8.07 (d, J = 4.7
benzo[d] MeOH/ Hz, 1H), 7.89 (d, J = imidazol- CO2 6.8 Hz, 1H),
7.87- 6-yl)pyridin-2- at 60 7.74 (m, 4H), 7.69 amine mL/min (s,
1H), 7.52-7.36 (m, 1H), 7.26-7.19 (m, 2H), 2.45 (s, 3H). 2.sup.nd
104 455.2 1H NMR e- (400 MHz, luting DMSO-d6) .delta. 9.32 peak (d,
J = 4.5 Hz, 1H), 8.30 (d, J = 1.3 Hz, 1H), 8.07 (d, J = 4.7 Hz,
1H), 7.89 (d, J = 6.8 Hz, 1H), 7.87- 7.74 (m, 4H), 7.69 (s, 1H),
7.52-7.36 (m, 1H), 7.26-7.19 (m, 2H), 2.45 (s, 3H).
[0664] Separation of atropisomers: The atropisomers of were
separated on OD-H SFC 5 uM 21.times.250 mm column. The conditions
for the separation of atropisomers and characterization data are
provided in the table below:
TABLE-US-00014 Separa- tion Peak Ex- Name method # ample MS NMR
4-[3-(5,8- OD-H 1.sup.st 105 473.2 .sup.1H NMR (400 MHz,
difluoroquinolin- SFC e- DMSO-d6) .delta. 9.31 4-yl)-2- 5 uM luting
(d, J = 4.5 Hz, 1H), methyl-7- 21 .times. peak 8.41 (hr s, 1H),
8.22 (4H-1,2,4- 250 mm (s, 1H), 8.09 (d, J = triazol-3-yl) column
4.5 Hz, 1H), 7.78 benzimidazol- in 30% (td, J = 9.5, 4.2 Hz,
5-yl]-3- MeOH/ 1H), 7.74 (dd, J = fluoropyridin- CO2 6.2, 0.9 Hz,
1H), 2-amine at 60 7.52 (s, 1H), 7.47 mL/min (ddd, J = 12.3, 8.8,
3.8 Hz, 1H), 6.84 (br s, 1H), 2.51 (s, 3H). 2.sup.nd 106 473.2
.sup.1H NMR (400 MHz, e- DMSO-d6) .delta. 9.31 luting (d, J = 4.5
Hz, 1H), peak 8.41 (br s, 1H), 8.22 (s, 1H), 8.09 (d, J = 4.5 Hz,
1H), 7.78 (td, J = 9.5, 4.2 Hz, 1H), 7.74 (dd, J = 6.2, 0.9 Hz,
1H), 7.52 (s, 1H), 7.47 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 6.84 (br
s, 1H), 2.51 (s, 3H). 4-[3-(3-chloro-8- Chiralpak 1.sup.st 107
489.2 .sup.1H NMR (400 MHz, fluoroquinolin-4- OD-H e- DMSO-d6)
.delta. 9.35 yl)-2-methyl-7- 150 .times. luting (s, 1H), 8.39 (s,
1H), (4H-1,2,4-triazol- 4.6 mm peak 8.22 (t, J = 1.5 Hz, 3-yl)
column in 1H), 7.79 (ddd, J = benzimidazol- 30% 10.7, 7.8, 1.2 Hz,
5-yl]-3- IPA/ 1H), 7.73 (d, J = 6.0 fluoropyridin- Heptane Hz, 1H),
7.67 (td, J = 2-amine at 7 mL/ 8.2, 5.0 Hz, 1H), min 7.51 (s, 1H),
7.13 (d, J = 8.4 Hz, 2H), 6.83 (t, J = 5.9 Hz, 1H), 2.43 (s, 3H).
2.sup.nd 108 489.2 .sup.1H NMR (400 MHz, e- DMSO-d6) .delta. 9.35
luting (s, 1H), 8.39 (s, 1H), peak 8.22 (t, J = 1.5 Hz, 1H), 7.79
(ddd, J = 10.7, 7.8, 1.2 Hz, 1H), 7.73 (d, J = 6.0 Hz, 1H), 7.67
(td, J = 8.2, 5.0 Hz, 1H), 7.51 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H),
6.83 (t, J = 5.9 Hz, 1H), 2.43 (s, 3H). 4-[3-(5,8- OD-H 1.sup.st
109 487.2 .sup.1H NMR (400 MHz, difluoroquinolin- SFC e- DMSO-d6)
.delta. 9.30 4-yl)-2-ethyl- 5 uM luting (d, J = 4.5 Hz, 1H), 7-(4H-
21 .times. peak 8.38 (s, 1H), 8.22 (s, 1,2,4-triazol-3- 250 mm 1H),
8.10 (d, J = 4.5 yl)benzimidazol- column in Hz, 1H), 7.83-7.71
5-yl]-3- 30% (m, 2H), 7.51 (t, J = fluoropyridin- MeOH/ 1.2 Hz,
1H), 7.46 2-amine CO2 (ddd, J = 12.4, 8.8, at 60 mL/ 3.8 Hz, 1H),
6.89 (t, min J = 6.0 Hz, 1H), 2.81- 2.68 (m, 2H), 1.27 (t, J = 7.5
Hz, 3H). 2.sup.nd 110 487.2 .sup.1H NMR (400 MHz, e- DMSO-d6)
.delta. 9.30 luting (d, J = 4.5 Hz, 1H), peak 8.38 (s, 1H), 8.22
(s, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.83-7.71 (m, 2H), 7.51 (t, J =
1.2 Hz, 1H), 7.46 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 6.89 (t, J =
6.0 Hz, 1H), 2.81- 2.68 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). 4-[3-(8-
OD-H 1.sup.st 111 503.2 .sup.1H NMR (400 MHz, chloro-5- SFC e-
DMSO-d6) .delta. 9.39 fluoroquinolin- 5 uM luting (d, J = 4.5 Hz,
1H), 4-yl)-2- 21 .times. peak 8.25 (t, J = 1.6 Hz, methyl-7-(5- 250
mm 1H), 8.16-8.10 (m, methyl-4H- column in 2H), 7.75 (d, J = 6.2
1,2,4-triazol-3- 30% Hz, 1H), 7.59 (dd, yl)benzimidazol- MeOH/ J =
1.7, 0.9 Hz, 1H), 5-yl]-3- CO2 7.49 (dd, J = 11.9, fluoropyridin-
at 60 8.6 Hz, 1H), 6.89 (t, 2-amine mL/min J = 6.0 Hz, 1H), 2.54
(s, 3H), 2.49 (s, 3H). 2.sup.nd 112 503.2 .sup.1H NMR (400 MHz, e-
DMSO-d6) .delta. 9.39 luting (d, J = 4.5 Hz, 1H), peak 8.25 (t, J =
1.6 Hz, 1H), 8.16-8.10 (m, 2H), 7.75 (d, J = 6.2 Hz, 1H), 7.59 (dd,
J = 1.7, 0.9 Hz, 1H), 7.49 (dd, J = 11.9, 8.6 Hz, 1H), 6.89 (t, J =
6.0 Hz, 1H), 2.54 (s, 3H), 2.49 (s, 3H). 4-[3-(5,8- OJ-H 1.sup.st
113 465.1 .sup.1H NMR (400 MHz, difluoroquinolin- SFC e- DMSO-d6)
.delta. 9.34 4-yl)-2-methyl- 5 uM luting (d, J = 4.5 Hz, 1H),
7-(4H-1,2,4- 21 .times. peak 8.71 (dd, J = 5.3, 0.8 triazol-3-yl)
250 mm Hz, 1H), 8.50 (s, benzimidazol- column in 1H), 8.43 (d, J =
1.7 5-yl]pyridine- 30% Hz, 1H), 8.39 (dd, 2-carbonitrile EtOH/ J =
2.0, 0.8 Hz, 1H), CO2 at 8.11-8.07 (m, 2H), 60 mL/ 7.87 (d, J = 1.7
Hz, min 1H), 7.79 (ddd, J = 10.1, 8.8, 4.3 Hz, 1H), 7.48 (ddd, J =
12.3, 8.8, 3.8 Hz, 1H), 2.52 (s, 3H). 2.sup.nd 114 465.1 .sup.1H
NMR (400 MHz, e- DMSO-d6) .delta. 9.34 luting (d, J = 4.5 Hz, 1H),
peak 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.50 (s, 1H), 8.43 (d, J = 1.7
Hz, 1H), 8.39 (dd, J = 2.0, 0.8 Hz, 1H), 8.11-8.07 (m, 2H), 7.87
(d, J = 1.7 Hz, 1H), 7.79 (ddd, J = 10.1, 8.8, 4.3 Hz, 1H), 7.48
(ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.52 (s, 3H). 4-(1-(5,7- OJ-H
1.sup.st 115 465.2 1H NMR (400 MHz, difluoroquinolin- SFC e-
DMSO-d6) .delta. 9.31 4-yl)-2-methyl-4- 5 uM luting (d, J = 4.6 Hz,
1H), (4H- 21 .times. peak 8.72 (dd, J = 5.3, 0.8 1,2,4-triazol- 250
mm Hz, 1H), 8.55-8.49 3-yl)-1H- column in (m, 1H), 8.43 (d, J =
benzo[d] 15% 1.7 Hz, 1H), 8.40 imidazol-6-yl) EtOH/ (dd, J = 1.9,
0.8 Hz, picolinonitrile CO2 at 1H), 8.09 (dd, J = 60 mL/ 5.3, 2.0
Hz, 1H), min 8.00 (ddd, J = 9.7, 2.5, 1.3 Hz, 1H), 7.97 (d, J = 4.6
Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.66 (ddd, J = 12.1, 9.3, 2.5
Hz, 1H), 2.52 (t, J = 0.5 Hz, 3H). 2.sup.nd 116 465.1 1H NMR (400
MHz, e- DMSO-d6) .delta. 9.31 luting (d, J = 4.6 Hz, 1H), peak 8.72
(dd, J = 5.3, 0.8 Hz, 1H), 8.55-8.49 (m, 1H), 8.43 (d, J = 1.7 Hz,
1H), 8.40 (dd, J = 1.9, 0.8 Hz, 1H), 8.09 (dd, J = 5.3, 2.0 Hz,
1H), 8.00 (ddd, J = 9.7, 2.5, 1.3 Hz, 1H), 7.97 (d, J = 4.6 Hz,
1H), 7.86 (d, J = 1.7 Hz, 1H), 7.66 (ddd, J = 12.1, 9.3, 2.5 Hz,
1H), 2.52 (t, J = 0.5 Hz, 3H). 4-(1-(5,7- AD-H 1.sup.st 117 473.2
1H NMR (400 MHz, difluoroquinolin- SFC e- DMSO-d6) .delta. 9.28
4-yl)-2-methyl- 5 uM luting (d, J = 4.6 Hz, 1H), 4-(4H-1,2,4- 21
.times. peak 8.41 (s, 1H), 8.22 (t, triazol- 250 mm J = 1.6 Hz,
1H), 8.01- 3-yl)-1H- column in 7.94 (m, 2H), 7.74 benzo[d] 35% (d,
J = 6.0 Hz, 1H), imidazol- MeOH/ 7.66 (ddd, J = 12.0,
fluoropyridin- CO2 9.2, 2.5 Hz, 1H), 2-amine at 60 mL/ 7.49 (s,
1H), 6.85 (t, min J = 5.8 Hz, 1H), 2.51 (s, 3H). 2.sup.nd 118 473.2
1H NMR (400 MHz, e- DMSO-d6) .delta. 9.28 luting (d, J = 4.6 Hz,
1H), peak 8.41 (s, 1H), 8.22 (t, J = 1.6 Hz, 1H), 8.01- 7.94 (m,
2H), 7.74 (d, J = 6.0 Hz, 1H), 7.66 (ddd, J = 12.0, 9.2, 2.5 Hz,
1H), 7.49 (s, 1H), 6.85 (t, J = 5.8 Hz, 1H), 2.51 (s, 3H).
4-(1-(5,8- AD-H 1.sup.st 119 505.1 1H NMR (400 MHz,
dichloroquinolin- SFC e- DMSO-d6) .delta. 9.38 4-yl)-2-methyl- 5 uM
luting (d, J = 4.4 Hz, 1H), 4-(4H-1,2,4- 21 .times. peak 8.45 (s,
1H), 8.25 (t, triazol-3-yl)-1H- 250 mm J = 1.6 Hz, 1H), 8.12
benzo[d] column in (d, J = 8.3 Hz, 1H), imidazol- 35% 8.09 (d, J =
4.4 Hz, 6-yl)-3- MeOH/ 1H), 7.78 (d, J = 8.3 fluoropyridin- CO2 Hz,
1H), 7.74 (d, J = 2-amine at 60 mL/ 6.2 Hz, 1H), 7.53- min 7.49 (m,
1H), 6.88 (t, J = 6.0 Hz, 1H), 2.48 (s, 3H). 2.sup.nd 120 505.1 1H
NMR (400 MHz, e- DMSO-d6) .delta. 9.38 luting (d, J = 4.4 Hz, 1H),
peak 8.45 (s, 1H), 8.25 (t, J = 1.6 Hz, 1H), 8.12 (d, J = 8.3 Hz,
1H), 8.09 (d, J = 4.4 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.74 (d, J
= 6.2 Hz, 1H), 7.53- 7.49 (m, 1H), 6.88 (t, J = 6.0 Hz, 1H), 2.48
(s, 3H). 4-(1-(5,8- OJ-H 1.sup.st 121 497.2 1H NMR (400 MHz,
dichloroquinolin- SFC e- DMSO-d6) .delta. 9.42 4-yl)-2-methyl- 5 uM
luting (d, J = 4.4 Hz, 1H), 4-(4H-1,2,4- 21 .times. peak 8.71 (dd,
J = 5.3, 0.8 triazol-3-yl)-1H- 250 mm Hz, 1H), 8.55 (s, benzo[d]
column 1H), 8.46 (d, J = 1.7 imidazol-6-yl) in 30% Hz, 1H), 8.40
(dd, picolinonitrile EtOH/ J = 2.0, 0.8 Hz, 1H), CO2 at 8.15-8.07
(m, 3H), 60 mL/ 7.86 (d, J = 1.7 Hz, min 1H), 7.78 (d, J = 8.3 Hz,
1H), 2.50 (s, 3H). 2.sup.nd 122 497.1 1H NMR (400 MHz, e- DMSO-d6)
.delta. 9.42 luting (d, J = 4.4 Hz, 1H), peak 8.71 (dd, J = 5.3,
0.8 Hz, 1H), 8.55 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.40 (dd, J =
2.0, 0.8 Hz, 1H), 8.15-8.07 (m, 3H), 7.86 (d, J = 1.7 Hz, 1H), 7.78
(d, J = 8.3 Hz, 1H), 2.50 (s, 3H).
4-(1-(5-chloro-8- OJ-H 1.sup.st 123 481.1 1H NMR (400 MHz,
fluoroquinolin-4- SFC e- DMSO-d6) .delta. 9.35 yl)-2-methyl-4- 5 uM
luting (d, J = 4.4 Hz, 1H), (4H-1,2,4- 21 .times. peak 8.71 (dd, J
= 5.3, 0.8 triazol-3-yl)-1H- 250 mm Hz, 1H), 8.51 (s, benzo[d]
column in 1H), 8.45 (d, J = 1.8 imidazol-6-yl) 30% Hz, 1H), 8.40
(dd, picolinonitrile EtOH/ J = 1.9, 0.8 Hz, 1H), CO2 at 8.12-8.07
(m, 2H), 60 mL/ 7.83 (d, J = 1.8 Hz, min 1H), 7.81 (d, J = 1.4 Hz,
1H), 7.80 (s, 1H), 2.48 (s, 3H). 2.sup.nd 124 481.1 1H NMR (400
MHz, e- DMSO-d6) .delta. 9.35 luting (d, J = 4.4 Hz, 1H), peak 8.71
(dd, J = 5.3, 0.8 Hz, 1H), 8.51 (s, 1H), 8.45 (d, J = 1.8 Hz, 1H),
8.40 (dd, J = 1.9, 0.8 Hz, 1H), 8.12-8.07 (m, 2H), 7.83 (d, J = 1.8
Hz, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.80 (s, 1H), 2.48 (s, 3H).
4-(1-(5- OJ-H 1.sup.st 125 463.1 1H NMR (400 MHz, chloroquinolin-
SFC e- DMSO-d6) .delta. 9.27 4-yl)-2-methyl- 5 uM luting (d, J =
4.6 Hz, 1H), 4-(4H-1,2,4- 21 .times. peak 8.70 (dd, J = 5.3, 0.8
triazol-3-yl)- 250 mm Hz, 1H), 8.40 (d, J = 1H-benzo[d] column in
1.8 Hz, 1H), 8.38 imidazol-6-yl) 30% (dd, J = 2.0, 0.8 Hz,
picolinonitrile EtOH/ 1H), 8.37-8.35 (m, CO2 at 1H), 8.06 (dd, J =
60 mL/ 5.3, 1.9 Hz, 1H), min 7.97 (d, J = 4.6 Hz, 1H), 7.73 (d, J =
1.8 Hz, 1H), 7.65 (dd, J = 9.0, 2.2 Hz, 1H), 7.40 (d, J = 9.0 Hz,
1H), 2.47 (s, 3H). 2.sup.nd 126 463.1 1H NMR (400 MHz, e- DMSO-d6)
.delta. 9.27 luting (d, J = 4.6 Hz, 1H), peak 8.70 (dd, J = 5.3,
0.8 Hz, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.38 (dd, J = 2.0, 0.8 Hz,
1H), 8.37-8.35 (m, 1H), 8.06 (dd, J = 5.3, 1.9 Hz, 1H), 7.97 (d, J
= 4.6 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.65 (dd, J = 9.0, 2.2 Hz,
1H), 7.40 (d, J = 9.0 Hz, 1H), 2.47 (s, 3H). 4-(1-(8- OJ-H 1.sup.st
127 447.2 1H NMR (400 MHz, fluoroquinolin- SFC e- DMSO-d6) .delta.
9.30 4-yl)-2-methyl- 5 uM luting (d, J = 4.5 Hz, 1H), 4-(4H-1,2,4-
21 .times. peak 8.71 (dd, J = 5.3, 0.8 triazol-3-yl)-1H- 250 mm Hz,
1H), 8.58 (s, benzo[d] column 1H), 8.48 (d, J = 1.7 imidazol-6-yl)
in 30% Hz, 1H), 8.39 (dd, picolinonitrile EtOH/ J = 2.0, 0.8 Hz,
1H), CO2 at 8.10-8.04 (m, 2H), 60 mL/ 7.81 (d, J = 1.7 Hz, min 1H),
7.76 (ddd, J = 10.8, 7.8, 1.2 Hz, 1H), 7.61 (td, J = 8.1, 5.0 Hz,
1H), 7.32-7.24 (m, 1H), 2.54 (s, 3H). 2.sup.nd 128 447.1 1H NMR
(400 MHz, e- DMSO-d6) .delta. 9.30 luting (d, J = 4.5 Hz, 1H), peak
8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.58 (s, 1H), 8.48 (d, J = 1.7 Hz,
1H), 8.39 (dd, J = 2.0, 0.8 Hz, 1H), 8.10-8.04 (m, 2H), 7.81 (d, J
= 1.7 Hz, 1H), 7.76 (ddd, J = 10.8, 7.8, 1.2 Hz, 1H), 7.61 (td, J =
8.1, 5.0 Hz, 1H), 7.32-7.24 (m, 1H), 2.54 (s, 3H). 4-(1-(8- OJ-H
1.sup.st 129 463.1 1H NMR (400 MHz, chloroquinolin- SFC e- DMSO-d6)
.delta. 9.36 4-yl)-2-methyl- 5 uM luting (d, J = 4.5 Hz, 1H),
4-(4H-1,2,4- 21 .times. peak 8.71 (dd, J = 5.3, 0.8 triazol-3-yl)-
250 mm Hz, 1H), 8.58 (s, 1H-benzo[d] column in 1H), 8.48 (d, J =
1.7 imidazol-6-yl) 30% Hz, 1H), 8.38 (dd, picolinonitrile EtOH/ J =
2.0, 0.8 Hz, 1H), CO2 at 8.11 (dd, J = 7.5, 1.2 60 mL/ Hz, 1H),
8.10-8.05 min (m, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.5,
7.5 Hz, 1H), 7.43 (dd, J = 8.5, 1.2 Hz, 1H), 2.53 (s, 3H). 2.sup.nd
130 463.1 1H NMR (400 MHz, e- DMSO-d6) .delta. 9.36 luting (d, J =
4.5 Hz, 1H), peak 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.58 (s, 1H),
8.48 (d, J = 1.7 Hz, 1H), 8.38 (dd, J = 2.0, 0.8 Hz, 1H), 8.11 (dd,
J = 7.5, 1.2 Hz, 1H), 8.10-8.05 (m, 2H), 7.81 (d, J = 1.7 Hz, 1H),
7.60 (dd, J = 8.5, 7.5 Hz, 1H), 7.43 (dd, J = 8.5, 1.2 Hz, 1H),
2.53 (s, 3H). 4-(1-(5- OJ-H 1.sup.st 131 447.1 1H NMR (400 MHz,
fluoroquinolin- SFC e- DMSO-d6) .delta. 9.30 4-yl)-2-methyl- 5 uM
luting (d, J = 4.5 Hz, 1H), 4-(4H-1,2,4- 21 .times. peak 8.71 (dd,
J = 5.3, 0.8 triazol-3-yl)- 250 mm Hz, 1H), 8.57 (s, 1H-benzo[d]
column in 1H), 8.46 (d, J = 1.7 imidazol-6-yl) 30% Hz, 1H), 8.41
(dd, picolinonitrile EtOH/ J = 2.0, 0.8 Hz, 1H), CO2 at 8.19-8.15
(m, 1H), 60 mL/ 8.09 (dd, J = 5.3, 1.9 min Hz, 1H), 8.00 (d, J =
4.6 Hz, 1H), 7.95- 7.87 (m, 2H), 7.48 (ddd, J = 12.4, 7.9, 1.0 Hz,
1H), 2.53 (s, 3H). 2.sup.nd 132 447.2 1H NMR (400 MHz, e- DMSO-d6)
.delta. 9.30 luting (d, J = 4.5 Hz, 1H), peak 8.71 (dd, J = 5.3,
0.8 Hz, 1H), 8.57 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.41 (dd, J =
2.0, 0.8 Hz, 1H), 8.19-8.15 (m, 1H), 8.09 (dd, J = 5.3, 1.9 Hz,
1H), 8.00 (d, J = 4.6 Hz, 1H), 7.95- 7.87 (m, 2H), 7.48 (ddd, J =
12.4, 7.9, 1.0 Hz, 1H), 2.53 (s, 3H). 5,8-difluoro-4- OJ-H 1.sup.st
133 458.1 1H NMR (400 MHz, (6-(2- SFC e- DMSO-d6) .delta. 9.33
fluoropyridin- 5 uM luting (d, J = 4.5 Hz, 1H), 4-yl)-2-methyl- 21
.times. peak 8.33 (s, 1H), 8.23 (d, 4-(4H-1,2,4- 250 mm J = 5.4 Hz,
2H), 8.08 triazol-3-yl)-1H- column in (d, J = 4.5 Hz, 1H), benzo[d]
30% 7.85-7.74 (m, 3H), imidazol-1-yl) EtOH/ 7.72 (dt, J = 5.5, 1.8
quinoline CO2 at Hz, 1H), 7.52 (s, 60 mL/ 1H), 7.47 (ddd, J = min
12.4, 8.8, 3.9 Hz, 1H), 2.46 (s, 3H). 2.sup.nd 134 458.1 1H NMR
(400 MHz, e- DMSO-d6) .delta. 9.33 luting (d, J = 4.5 Hz, 1H), peak
8.39 (s, 1H), 8.35 (d, J = 1.7 Hz, 1H), 8.23 (d, J = 5.4 Hz, 1H),
8.08 (d, J = 4.5 Hz, 1H), 7.85-7.74 (m, 2H), 7.72 (dt, J = 5.4, 1.8
Hz, 1H), 7.52 (dt, J = 1.5, 0.7 Hz, 1H), 7.48 (ddd, J = 12.3, 8.8,
3.8 Hz, 1H), 2.48 (s, 3H). 4-(1-(8-chloro-5- OJ-H 1.sup.st 135
481.1 1H NMR (400 MHz, fluoroquinolin-4- SFC e- DMSO-d6) .delta.
9.42 yl)-2-methyl- 5 uM luting (d, J = 4.5 Hz, 1H), 4-(4H-1,2,4- 21
.times. peak 8.71 (dd, J = 5.3, 0.8 triazol-3-yl)- 250 mm Hz, 1H),
8.53 (s, 1H-benzo[d] column in 1H), 8.44 (d, J = 1.8 imidazol-6-yl)
30% Hz, 1H), 8.39 (dd, picolinonitrile EtOH/ J = 1.9, 0.8 Hz, 1H),
CO2 at 8.16-8.11 (m, 2H), 60 mL/ 8.08 (dd, J = 5.3, 1.9 min Hz,
1H), 7.89 (d, J = 1.7 Hz, 1H), 7.49 (dd, J = 11.9, 8.6 Hz, 1H),
2.53 (s, 3H). 2.sup.nd 136 481.1 1H NMR (400 MHz, e- DMSO-d6)
.delta. 9.42 luting (d, J = 4.5 Hz, 1H), peak 8.71 (dd, J = 5.3,
0.8 Hz, 1H), 8.53 (s, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.39 (dd, J =
1.9, 0.8 Hz, 1H), 8.16-8.11 (m, 2H), 8.08 (dd, J = 5.3, 1.9 Hz,
1H), 7.89 (d, J = 1.7 Hz, 1H), 7.49 (dd, J = 11.9, 8.6 Hz, 1H),
2.53 (s, 3H). 8-chloro-4-(6-(3- OJ-H 1.sup.st 137 456.1 1H NMR (400
MHz, fluoropyridin- SFC e- DMSO-d6) .delta. 9.33 4-yl)-2-methyl- 5
uM luting (dd, J = 4.5, 0.6 Hz, 4-(4H-1,2,4- 21 .times. peak 1H),
8.60 (d, J = 2.6 triazol-3-yl)- 250 mm Hz, 1H), 8.51 (s,
1H-benzo[d] column in 1H), 8.43-8.39 (m, imidazol-1- 20% 1H), 8.30
(d, J = 1.9 yl)quinoline MeOH/ Hz, 1H), 8.11 (dt, CO2 J = 7.4, 1.0
Hz, 1H), at 60 mL/ 8.08 (d, J = 4.5 Hz, min 1H), 7.63-7.55 (m, 2H),
7.49 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H). 2.sup.nd 138
456.1 1H NMR (400 MHz, e- DMSO-d6) .delta. 9.33 luting (dd, J =
4.5, 0.6 Hz, peak 1H), 8.60 (d, J = 2.6 Hz, 1H), 8.51 (s, 1H),
8.43-8.39 (m, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.11 (dt, J = 7.4, 1.0
Hz, 1H), 8.08 (d, J = 4.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.49 (s, 1H),
7.42 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H). 5,8-difluoro-4- OJ-H
1.sup.st 139 440.2 1H NMR (400 MHz, (2-methyl-6- SFC e- DMSO-d6)
.delta. 9.33 (pyridin-4- 5 uM luting (d, J = 4.5 Hz, 1H),
yl)-4-(4H- 21 .times. peak 8.78-8.73 (m, 2H), 1,2,4- 250 mm 8.46
(dd, J = 1.8, 0.6 triazol-3-yl)- column Hz, 1H), 8.23-8.16
1H-benzo[d] in 30% (m, 2H), 8.09 (d, J = imidazol-1- MeOH/ 4.5 Hz,
1H), 7.91 yl)quinoline CO2 (dd, J = 1.8, 0.6 Hz, at 60 mL/ 1H),
7.79 (td, J = min 9.5, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3, 8.7, 3.8
Hz, 1H), 2.50 (s, 3H). 2.sup.nd 140 440.1 1H NMR (400 MHz,
e- DMSO-d6) .delta. 9.33 luting (d, J = 4.5 Hz, 1H), peak 8.78-8.73
(m, 2H), 8.46 (dd, J = 1.8, 0.6 Hz, 1H), 8.23-8.16 (m, 2H), 8.09
(d, J = 4.5 Hz, 1H), 7.91 (dd, J = 1.8, 0.6 Hz, 1H), 7.79 (td, J =
9.5, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3, 8.7, 3.8 Hz, 1H), 2.50 (s,
3H). 5,8-difluoro-4- OD-H 1.sup.st 141 454.2 1H NMR (400 MHz,
(2-methyl-6-(2- SFC e- DMSO-d6) .delta. 9.34 methylpyridin- 5 uM
luting (d, J = 4.5 Hz, 1H), 4-yl)-4-(4H- 21 .times. peak 8.70 (dd,
J = 6.4, 0.6 1,2,4-triazol-3- 250 mm Hz, 1H), 8.48 (d, J =
yl)-1H-benzo[d] column 1.8 Hz, 1H), 8.44 (s, imidazol-1- in 30%
1H), 8.25 (d, J = 1.9 yl)quinoline EtOH/ Hz, 1H), 8.15 (dd, CO2 at
J = 6.3, 2.0 Hz, 1H), 60 mL/ 8.10 (d, J = 4.5 Hz, min 1H), 7.90 (d,
J = 1.8 Hz, 1H), 7.79 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H), 7.47 (ddd,
J = 12.3, 8.8, 3.8 Hz, 1H), 2.67 (s, 3H), 2.48 (s, 3H). 2.sup.nd
142 454.2 1H NMR (400 MHz, e- DMSO-d6) .delta. 9.34 luting (d, J =
4.5 Hz, 1H), peak 8.70 (dd, J = 6.4, 0.6 Hz, 1H), 8.48 (d, J = 1.8
Hz, 1H), 8.44 (s, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.15 (dd, J = 6.3,
2.0 Hz, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H),
7.79 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3, 8.8,
3.8 Hz, 1H), 2.67 (s, 3H), 2.48 (s, 3H).
[0665] From the foregoing it will be appreciated that, although
specific embodiments have been described herein for purposes of
illustration, various modifications may be made without deviating
from the spirit and scope of the present application.
Biological Examples
[0666] The compounds of formula (I) were characterized for their
enzymatic activity against the PI3K isoforms. The activities were
measured using a time-resolved fluorescence resonance energy
transfer (TR-FRET) assay. TR-FRET monitored the formation of
3,4,5-inositol triphosphate molecule that competed with
fluorescently labeled PIPS for binding to the GRP-1 pleckstrin
homology domain protein. An increase in phosphatidylinositide
3-phosphate product resulted in a decrease in TR-FRET signal as the
labeled fluorophore was displaced from the GRP-1 protein binding
site.
[0667] Class I PI3K isoforms were expressed and purified as
heterodimeric recombinant proteins. All assay reagents and buffers
for the TR-FRET assay were purchased from Millipore. PI3K isoforms
were assayed under initial rate conditions in the presence of 25 mM
Hepes (pH 7.4), and 2.times. Km ATP (75-500 .mu.M), 2 .mu.M PIP2,
5% glycerol, 5 mM MgCl.sub.2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM
dithiothreitol, and 1% (v/v) DMSO at the following concentrations
for each isoform: PI3K.alpha., PI3K.beta., and PI3K.delta. between
25 and 50 pM, and PI3K.gamma. at 2 nM. The compounds were added to
the assay solution and incubated for 30 minutes at 25.degree. C.
The reactions were terminated with a final concentration of 10 mM
EDTA, 10 nM labeled-PIPS, and 35 nM Europium labeled GRP-1 detector
protein before reading TR-FRET on an Envision plate reader (Ex: 340
nm; Em: 615/665 nm; 100 .mu.s delay and 500 .mu.s read window).
[0668] The results were normalized based on positive (1 .mu.M
wortmanin) and negative (DMSO) controls, and the IC.sub.50 values
for PI3K .alpha., .beta., .delta., and .gamma. were calculated from
the fit of the dose-response curves to a four-parameter equation.
These assays generally produced results within 3-fold of the
reported mean.
TABLE-US-00015 Compound IC.sub.50-PIP-Beta (nM) 1 34 2 13 3 2800 4
20 5 86 6 36 7 16 8 82 9 950 10 1600 11 3 12 340 13 15 14 62 15 150
16 51 17 150 18 23 19 12 20 1100 21 1300 22 1100 23 96 24 22 25 6
26 13 27 5 28 6 29 6 30 8 31 89 32 6 33 110 34 26 35 22 36 250 37 4
38 7 39 5 40 5 41 27 42 10 43 30 44 4 45 8 46 1100 47 46 48 10 49
170 50 17 51 3 52 330 53 180 54 36 55 19 56 9 57 290 58 10 59 270
60 420 61 35 62 8 63 7 64 200 65 16 66 140 67 8 68 35 69 47 70 13
71 13 72 10 73 8 74 29 75 3 76 50 77 1400 78 5 79 8 80 2 81 15 82
120 83 2 84 4 85 3 86 7 87 12 88 110 89 3 90 340 91 19 92 51 93 5
94 8 95 5 96 7 97 31 98 6 99 29 100 320 101 2800 102 11 103 210 104
9 105 1400 106 3 107 29 108 810 109 2600 110 2 111 2500 112 5 113 2
114 560 115 3 116 30 117 4 118 35 119 87 120 4 121 1 122 28 123 8
124 160 125 110 126 780 127 9 128 360 129 3 130 57 131 2 132 54 133
2 134 400 135 4 136 220 137 10 138 99 139 6 140 540 141 120 142 11
143 6 144 18 145 2 146 200 147 4 148 16 149 4 150 13 151 80 152 10
153 7 154 9 155 62 156 12 157 460 158 7 159 5 160 7 161 6 162 10
163 120 164 10 165 480 166 70 167 10
[0669] From the foregoing it will be appreciated that, although
specific embodiments have been described herein for purposes of
illustration, various modifications may be made without deviating
from the spirit and scope of the present application.
* * * * *